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OPIATE ANALGESICS

1. Introduction

Despite that Webster’s Dictionary devotes a full column of exceedingly fine print
to definitions of the word pain, it is all too easy to recognize that discomfiting sen-
sation. Pain, which plays an important role in relations with the environment,
commonly comprises the first and most immediate response to a new or poten-
tially injurious circumstance. Almost every explanation of the term invokes
the reaction to touching a finger to a hot stove. The sensation that results
from that contact leads to quick withdrawal of the finger and, thus, avoidance
of a burn. Pain-causing stimuli are not only restricted to the exterior environ-
ment but can as well originate at an organ or other structure within the body
as an alert that something within is amiss. The immediate signal from an
event that will be manifested as pain travels up the autonomic nervous system
to the cerebral medulla. The signal for the required response, pulling back the
finger, is then sent back via the autonomic nervous system. The signal is also
communicated to the central nervous system (CNS) where it elicits conscious
recognition of pain. Although pain plays a vital role in day-to-day function, a pro-
blem often originates when the pain-causing stimulus persists as in the chronic
pain from an inflamed appendix, or in cases where the sensation persists long
after the stimulus has been withdrawn. Drugs used to treat pain fall into
three categories based on their mode of action. The local anesthetics block
nerve transmission from the site of the injury, effectively numbing the area.
These agents are relatively short acting and of little use in treating pain of
any duration. The so-called peripheral analgesics that comprise the corticoster-
oids and the nonsteroidal antiinflammatory drug agents (NSAIDs) act at the site
of the pain stimulus by inhibiting the synthesis of thromoxanes and prostaglan-
dins. The opiates, sometimes, classed as central analgesics, act at the level of the
CNS, where they alter the conscious perception of the pain. Although opiate, or
central analgesics, are sometimes referred to as narcotics, that term will not be
used in what follows.

2. A Thumbnail History of the Development of Opiates

The origin of the discovery of the opiates, drugs that have proven useful for treat-
ing deep and persistent pain, is as the cliche has it, lost in the mists of time.
There is thus no record of the person who first ingested the sap exuded on the
seedpods of the poppy papaver somniferum and noted that doing so made him
sleepy. That dried sap, or opium, became an article of commerce as early as
the second millennium B.C. as a consequence of its soporific and narcotic activity
(1). The drug constituted one of the few items that had true physiological activity
in pharmacopeias well into the nineteenth century. Abuse of the drug because of
its narcotic activity led to recognition of its propensity to cause addiction. Modern
research has revealed that the crude drug may contain as many as 20 compounds
with very closely related chemical structures. The most active of those com-
pounds, morphine, was first isolated from the mixture in crystalline form in
1803 by Friedrich Sertuner. The name, morphine, after the Greek god of sleep

Kirk-Othmer Encyclopedia of Chemical Technology. Copyright John Wiley & Sons, Inc. All rights reserved.
2 OPIATE ANALGESICS

Morpheus, derives from what was considered, at the time, the principal activity
of the drug. This purified compound replaced opium in many applications such as
analgesia because doses could be more easily and reliably gauged with the pure
crystalline substance. One of the minor constituents that accompanied morphine
in opium later became a drug in its own right. This compound, codeine, although
somewhat less potent than its parent, is more readily absorbed on oral adminis-
tration. It can be prepared in a single step from morphine as it is simply the
methyl ether of the latter. From that point until about 1930, chemists in various
laboratories carried out a variety of experiments to modify the structure of mor-
phine to try to find drugs with superior activity and lower addiction potential.
The chemical structure of the compound was, however, unknown at the time,
beyond its relative empirical formula. The very concept of molecular structure
was in fact not fully recognized until the end of the nineteenth century (2).
These transformations thus involved largely treating morphine with selected
reagents and isolating the products, if any. The structures of these derivatives
were thus not assigned until the structure of morphine itself was announced
in 1927 by Robert Robison (later Sir) and J. M. Gulland in 1925 and indepen-
dently by Sch€opf (3). A relatively small number of opiates derived from morphine
was then synthesized in the pharmaceutical and academic laboratories. The
development by Grewe of a total synthesis of a compound that incorporated a
major portion of the morphine carbon skeleton, a so-called morphinan, from
ordinary laboratory chemicals, opened the door for a large number of opiates,
many of which found uses in treating pain.

3. Mode of Action of Opiates

The signal elicited by a painful event, as noted, travels to both the autonomic and
the central nervous system, the latter encompassing the brain. Several regions in
the brain, richly endowed with endorphin receptors, are involved in recognizing
pain messages. Activation of those areas by the pain-elicited signal leads to the
conscious recognition of pain. Binding of an opiate to endorphin receptors does
not actually block the perception of pain; that binding instead modulates the per-
ception of pain as an unpleasant and in the extreme case, unbearable sensation.
The individual treated with an opiate usually recognizes that the pain is still pre-
sent but no longer interprets that as an unpleasant sensation.
3.1. Opiate Receptors. Scientists who studied the chemistry of opiates
had for some time considered the likelihood that these molecules acted via a
receptor. This hunch was confirmed in 1973 when Pert and Snyder demonstrated
the existence of a site in nervous tissue that stereospecifically bound a tritiaded
sample of the opiate antagonist naloxone (4). These receptors are widely distrib-
uted in nervous tissues particularly those in the brain and the gastrointestinal
(GI) tract. The presence of such structures was something of a puzzle because
they had obviously evolved in the absence of opiates. This apparent paradox
was laid to rest in 1976 with the discovery of endogenous five amino acid peptides
dubbed enkephalins that bound to the receptor (5). This peptide was found to be
but one of a group of small peptides, which also includes dynorphins, known
collectively as endorphins.
OPIATE ANALGESICS 3

3.2. Receptor Classification. The opiate receptor actually occurs as a


number of subtypes; binding with each of these leads to a somewhat different set
of biological effects. The disparity of the pharmacological activity of some opiate
analogues from effects of the prototype, morphine, is attributed to binding to
these subtypes. Each of these receptor variants occurs as yet further subtypes:

 The m (mu) receptor accounts for most of the activity of classic opiates. It is
found mainly in the brain, spinal cord, and GI tract. Binding to this struc-
ture results in analgesia. The classic opiate side effects that include
respiratory depression, constipation, and physical dependence are attribu-
ted to binding to this receptor.
 The k (kappa) receptor is found mainly in the brain and spinal cord.
Binding results in analgesia and sedation. It does not apparently lead to
physical dependence.
 The d (delta) receptor is found mainly in the brain. Binding leads to analge-
sia but also to dependence.

3.3. Addiction to Opiates. No discussion of opiates is complete without


touching on the propensity of these drugs to lead to the development of physical
and psychological dependence. Two diverse populations develop addiction: The
most familiar group comprises individuals who consume opiates for the thrill.
Another and possibly larger group is made up of patients who consume opiates
on a long-term basis to alleviate chronic pain. Many opiates act as euphoriants as
well as analgesics. Heroin’s popularity among addicts, for example, is because
the compound readily crosses the blood brain barrier where it is metabolized
to morphine. The immediate high levels of the opiate in the brain that can be
achieved on intravenous administration provide the ‘‘rush’’ so eagerly sought
by addicts. Feedback inhibition consequent to chronic occupation of opiate recep-
tors leads to suppression of the release of endogenous endorphins reinforcing the
need for more opiate. Administration of a typical opiate for a prolonged period
whether for therapeutic or recreational use thus leads to habituation where
increasingly higher doses are required for the desired effect be that analgesia
or euphoria. An abrupt halt of administration of an opiate to a drug-dependent
individual will cause first psychological craving for the prewithdrawal euphor-
iant state. The physical symptoms suffered by addicts on withdrawal of opiates
include severe muscle pains, abdominal cramping, diarrhea, nausea, and vomit-
ing. Many substance abuse centers currently treat opiate-dependent individuals
with a drug that binds to opiate receptors without eliciting the euphoriant
effects. Synthetic opiates such as methadone, or buprenorphine, enables drug
dependents to resume their normal life despite that they are still addicted.
3.4. Drug-finding Screens. Most assays for testing compounds for the
pain-killing properties rely on presenting a test animal, most commonly, a mouse
or rat, with a painful stimulus. The test subject is then observed for an overt
reaction to pain and to an increase in the time before the animal reacts (latency
period). The more frequently used in vivo assays have a venerable origin as they
were originally published back in the middle of the twentieth century. The fact
that commercially manufactured apparatus for automating those tests currently
4 OPIATE ANALGESICS

available indicates that these assays or modified versions are still used to screen
for new analgesics.

1. In the hot plate test, the animal is either placed on a hot plate heated to
50 C or on a cold plate that gradually reaches that temperature. An
untreated rodent will respond by jumping to try to avoid the painful
stimulus or under certain conditions liking the sole of its hind paw.
2. The tail flick assay involves focusing a hot beam onto the tail of the rodent.
An untreated animal will respond by flicking that tail.
3. The writhing assay involves injecting an irritating substance, typically
hydrochloric or acetic acid into the rodent’s peritoneum. Untreated rodents
will respond by writhing.
4. Follow-up tests to exclude analgesics that act by other mechanisms such as
NSAIDs will involve opiate receptor binding assays as well as reversal of
the analgesic action by naloxone.

4. Opiates Derived From Morphine

A typical sample of crude opium will contain as many as 20 related alkaloids,


approximately 10% of which comprises morphine and 0.5% codeine. These com-
pounds, like most natural products, occurs in nature as a single diastereoisomer;
the isomeric mirror image morphine molecule in which the absolute configura-
tion of each chiral center is reversed, prepared by Brossi and his colleagues
(6), shows little if any analgesic activity.
Morphine (1) is customarily depicted as in the ‘‘Conventional’’ structure in
Figure 1. The three-dimensional version (Stereochemical) reveals a feature
essential for efficient receptor binding. The sole benzene ring in the molecule
is locked into a perpendicular (axial) configuration to the plane of the fused
piperidine ring at the carbon atom furthest from the ring-nitrogen.
Morphine proper is not particularly well absorbed when taken by mouth as
shown by the fact that only half or less of an oral dose reaches the CNS, attrib-
uted in part to the presence of the polar phenolic hydroxyl on the benzene ring.

H3C
H3C
N
N

O OH

O OH OH
HO

Conventional Stereochemical
Morphine
(1)

Fig. 1. Morphine.
OPIATE ANALGESICS 5

Codeine (2), in which that hydroxyl is covered by an ethereal methyl group,


occurs in opium as a minor constituent. Close to 90% of an oral dose of codeine
reaches the target. The product of reaction of morphine with acetic anhydride,
diacetyl morphine (3) is one of the first derivates to come out of a program for
preparing less addictive derivatives. As noted, this drug is a poster child for
the law of unintended consequences. This drug, dubbed heroin, was found to
be somewhat more potent than morphine itself. The lower doses that were
required for analgesia led to the naı̈ve assumption that the smaller amounts
required for treating pain would lead to less addiction.

H3C H3C
N N

H3CO O OH CH3COO O OCOCH3

Codeine Di-acetylmorphine (Heroin)


(2) (3)

Despite the problem posed by its propensity to cause drug dependence, mor-
phine, was and is still an indispensable drug for treating severe acute or chronic
pain. This dilemma has led to continuing research aimed at providing derivatives
or totally synthetic compounds that act on the same receptor but do not cause the
dependence that typify morphine itself. Virtually all of the analogues obtained by
modifying that opiate were prepared decades before the isolation of opiate recep-
tors. It was found much more recently that the analgesics in this class bound to
the m (named after morphine) receptors. Most analogues were prepared by rela-
tively simple chemical manipulations. Simple reduction of the double bond in
morphine and subsequent oxidation of the hydroxyl group in the same ring
leads to hydromorphone (4) (7). The same sequence starting with codeine leads
to hydrocodone (5) (8,9). Both compounds are more potent than the parent
molecules; the latter is often prescribed as a cough suppressant.

H3C H3C
N N

HO O O H3CO O O

Hydromorphone Hydrocodone
(4) (5)

A somewhat more complex sequences are required for preparing derivatives


that incorporate more deep-seated changes. In brief outline form, the synthesis
of metopon involves first opening of the oxygen-containing ring in hydrocodone.
A methyl group is then introduced at the carbon next to the ketone. The
6 OPIATE ANALGESICS

H3C H3C
H3C N
N
N

H3CO O
O H3CO OH O CH3 O
H3CO O
Metopon
Hydrocodone
(6)

Fig. 2. Synthesis of metopon.

five-membered ring is then reestablished. The fact that the final product,
metopon (10) (6) (Fig. 2), shows much the same analgesic activity as hydrocodone
showed that biological activity was retained in the face of substantial structural
changes. All these compounds interact largely with m receptors and show the
same addicting properties as morphine.

H
N
N

HO O OH
HO O OH

Norhydromorphine Nalorphine
(7) (8)

Changing the substituent on nitrogen brings about a qualitative change of


the biological activity. The methyl group on nitrogen can be removed by one of
several procedures to afford norhydromorphine (7). Alkylating the resulting sec-
ondary amine with an allyl halide afford nalorphine (8) (11). This compound acts
as an opiate antagonist when tested at low doses in an in vivo analgesic assay;
the same holds true at low concentrations in some in vitro assays. Analgesic
activity is, however, restored when nalorphine is tested at higher doses.
Although nalorphine was equipotent with morphine in humans, withdrawal
symptoms in patients seemed milder than those from morphine. The drug’s
hallucinogenic properties however prevented its routine use in the clinic. This
observation that an opiate that acts as a mixed agonist-antagonist seemed to
be less addictive steered the direction of opiate research for decades to come.

5. Opiates Derived From Thebaine

Thebaine (9) comprises 1 of the 20 or so minor alkaloids that accompany


morphine in opium from Papaver somniferum. This analogue of morphine that
OPIATE ANALGESICS 7

H3C
H3C N
H3C H3C HO
N
N N OH
OH
O OCH3 H2O 2 O OCH3

H3CO O O
H3CO O OCH3 OCH3 OCH3

Conventional Stereochemical Hydroxydehydrocodeinone


Thebaine
(9) (10)

Fig. 3. Formation of hydroxydehydrocodeinone from thebaine.

encompasses a conjugated diene that provides a reactive site for preparing


unique analogues. The observation that the dried sap from selected cultivars of
the poppy Papaver bracteum contains as much 20% of this alkaloid opened the
way for the synthesis of a series of novel derivatives. Oxidation of thebaine
with hydrogen peroxide leads to the addition of oxygen across the ends of the
diene system. This reaction in essence results in the addition of a hydroxyl
group at each end of that diene. The hydroxyl on the carbon that bears a methoxy
group converts that site to what is in effect a labile methyl acetal. This readily
reverts to a ketone in the presence of water. The overall result of this oxidation
amounts to the formation of hydroxydehydrocodeinone (10) (Fig. 3). The stereo-
chemical representation of thebaine emphasizes the fact that the oxidation
involves addition to the more open face of that molecule. It is of interest to
note in passing that commercial codeine is actually prepared from thebaine in
just two steps.
Relatively straightforward chemistry starting from hydroxydehydro-
codeinone leads to the widely used analgesics oxycodone (11) and oxymorphone
(12). The former is the active constituent in the much maligned, and
abused, drug OxyContin (Purdue Pharma, Stamford, CT). These opiates have
much the same activities as their counterparts lacking the extra hydroxyl
group. They also, however, have the same propensity for causing drug
dependence.
Replacing the methyl group on nitrogen by somewhat more complex alkyl
side chains results in qualitative changes of biological activity. The drug in
which the side chain on nitrogen consists of an allyl group, naloxone (13) (12),
is a virtually pure narcotic antagonist that shows no analgesic activity in either
laboratory assays or in humans. The compound does however strongly bind to
opiate receptors. This drug, rather than an opiate agonist, was used in the
work that led to the identification of those receptors. Administration of
naloxone to an addict by injection (the drug is at best poorly absorbed when
taken by mouth) causes virtually immediate withdrawal symptoms. The drug
does, however, find clinical use in treating emergency cases of acute overdoses
of opiate.
8 OPIATE ANALGESICS

H3C
H3C
N
N
OH
OH

HO O O
H3CO O O

Oxycodone Oxymorphone
(11) (12)

N N N
OH OH OH

HO O O HO O O O OH
HO

Naloxone Naltrexone Nalbufine


(13) (14) (15)

Variants on this theme in which other alkyl groups replace the methyl
group on nitrogen exhibit differing mixtures of agonist/antagonist activities.
Naltrexone (14) (12), in which a cyclopropyl group replaces the methyl group
on nitrogen, binds to both m and k receptors and is used largely to help addicts
overcome their dependence. The drug is also used to treat alcohol dependence
although it does so by some unknown mechanism. The closely related drug nal-
bufine (15) (13) in which the double bond is replaced by a cyclobutyl ring is also a
mixed agonist-antagonist in laboratory models. Analgesia, however, predomi-
nates in humans. This drug interestingly does not appear on the FDA list of con-
trolled substances.
Replacing the ring carbonyl by a hydrazone affords naloxazone (16) (14).
Like its precursor, this compound is an opiate antagonist. The drug is however
strictly a laboratory tool because it forms a permanent covalent bond with the
opiate receptors and more or less permanently inactivates those structures.
The compound, here named ‘‘aminocodone,’’ (17) in which an amino group
replaces the hydroxyl group in oxycodone can be prepared from thebaine by a
somewhat more involved scheme than that used for introducing oxygen at that
position (see Fig. 3). Adding a five-carbon side chain to the primary amino group
produces pentamorphone (18) (15). This product is a potent analgesic in humans.
It has not been introduced in the market because it offers no advantages over
currently available drugs.
OPIATE ANALGESICS 9

CH3 CH3
CH4
N N N
OH NH2 NH

O H3CO O O O
HO N HO O
H2N “Aminocodone”
Naloxazone Pentamorphone
(16) (17) (18)

H3C
N

OH CH3

CH3
HO O OCH3

Etorphine
(19)

The double-bond array in thebaine (diene), which reacts with hydrogen per-
oxide, will also accept an intermediate that features an activated double bond.
This results in the formation of two new carbon-to-carbon covalent bonds and
thus a new ring that spans the ends of the reactive diene. Further transforma-
tion of that condensation product affords etorphine (19). This product shows clas-
sic opiate activity; the potency of etorphine ranges between 1,000 and 10,000 that
of morphine in animals including humans. The drug is used mainly to knock
down large animals to permit physiological studies.

6. Totally Synthetic Opiates

The development of a scheme for preparing opiate analogues lacking the fused
five-membered, oxygen-containing ring from so-called coal-tar intermediates
led to the synthesis of a host of analogues, some of which are still used in the
clinic. This also led to the synthesis of opiates with yet further simplified struc-
tures some of which hardly resemble morphine. Lest this narrative leaves the
impression of a smooth progression toward ever simpler molecules, it should
be noted that discovery of some of the abbreviated molecules, such as methadone
and meperidine, occurred out of order chronologically.
6.1. Morphinans. Opiates lacking the fused oxygen-containing, five-
membered ring named morphinans are prepared in approximately six steps
from readily available so-called coal tar starting materials. The key step in
this sequence involves formation of the morphine carbon nucleus. The product
10 OPIATE ANALGESICS

H3C H3C H3C


N N N

HO H3CO H3CO
R = CH3, Cyclizaton Product Dextromethorphan
Levomethorphan
R = H, Racemorphan (20) (21)

H3C
N N

HO H3CO
Levorphanol Levallorphan
(22) (23)

Fig. 4. Cyclization product.

from that reaction, dubbed ‘‘Cyclization Product’’ in Figure 4, is obtained as a 1:1


mixture of the two possible mirror image forms. The product in which the methyl
group on oxygen has been removed comprises the potent opiate racemorphan
(16), the name pointing to the fact that the drug comprises the mixture of the
two stereoisomers. Each of the two isomers of the initial cyclization product exhi-
bits somewhat different biological activities reflecting the fact that binding to
receptors involves interaction with a structure that is itself composed of a
single one of the two possible isomers of amino acids. Each of the two mirror
isomers of the cyclization product comprises a drug in its own right. Levomethor-
phan (20) (17), the isomer that rotates polarized light to the left, is a potent
opiate analgesic; the derivative lacking the methyl group on oxygen levorphanol
is used in as a preopreative analgesic. Dextromethorphan (21), the other isomer,
shows little if any analgesic activity. The drug does however suppress the cough
reflex and comprises the anitussive agent present in many over-the-counter cold
remedies. The N-allyl derivative acts as an opiate antagonist and has been used
to counteract the respiratory depression resulting from opiates. It is of note that
all these dugs interact largely with m opiate receptors and elicit the side effects
typical for that class of analgesics.
A morphinan in which one of the rings is contracted from six to five atoms is
said to have the same analgesic effect and potency as morphine (18). By the same
token, a compound in which the fused piperidine is opened and a benzene ring is
attached to nitrogen is described as having the same analgesic activity as mor-
phine but at one third the dose (19) (Fig. 5).
The presence of a hydroxyl group at the position equivalent to the corre-
sponding function in opiates derived from thebaine has a similar effect on
the biological activity of those products. The scheme for preparing such
OPIATE ANALGESICS 11

CH3
CH3
N
N
OH

CH3
HO HO
Ring Contracted Ring Opened

Fig. 5. Ring contraction and opening.

hydroxylated derivatives is considerably more complex (about 12 steps versus 6)


than that used to synthesize the simpler morphinans. The product from that
synthesis, butorphanol, shows mixed opiate agonist–antagonist activity, like
its thebaine-derived hydroxylated counterparts. Although butorphanol (24)
binds to both m and k opiate receptors, the compound acts as a m-analgesic in
humans. The drug is also available in the form of an intranasal spray for treating
migraine headaches.

N
OH

HO
Butorphanol
(24)

6.2. Benzomorphans. A synthesis based closely on that used to prepare


morphinans provides access to opiates that lack yet another of the rings present
in morphine: the benzomorphans (Fig. 6). Two carbon atoms from the omitted
ring are retained in the form of a pair of methyl groups at the former ring carbon
atoms. Many drugs in this class carry somewhat more elaborate substituents on
nitrogen than the opiates described previously. The parent compound, which has
never acquired a generic name, is an opiate with potency in the same range as
morphine. The substituents on nitrogen in this series too play an important part
in both the qualitative and the quantitative activity of benzomorphans. The ana-
logue bearing a phenylethyl group, phenazocine (26) (20), is, for example, some
ten times as potent as morphine. The side effects elicited by this drug are very
similar to those caused by morphine. Pentazocine (27) (21) was one of the first
analgesic opiates with a reduced propensity to cause dependence. The compound
acts mainly by binding to k receptors. The drug was not included in the FDA list
12 OPIATE ANALGESICS

CH3
N N N

CH3 CH3 CH3

CH3 CH3 CH3


HO HO HO
Parent Benzomorphan Phenazocine Pentazocine
(25) (26) (27)

O N N
NH2
CH3 CH3

CH3 CH3
CH3
HO HO
HO Cyclazocine
Dezocine Ketazocine
(28) (29) (30)

Fig. 6. Benzomorphans.

of scheduled drugs when it was first introduced. It was however subsequently


listed although in the least stringent category in response to reports that the
drug was abused by some individuals. Cyclazocine (30) binds to both m and
k opiate receptors, whereas its close analogue ketazocine (22) binds to mostly
k sites (those receptors were in fact named after ketazocine). Neither drug was
ever approved by regulatory bodies because of their prominent psychotomimetic
and halucinogenic side effects. The chemical structure of the opiate dezocine (23)
shows some remote resemblance to that of the benzomorphans. The synthetic
route to this marketed drug differs significantly from that used to prepare the
benzomorphans. The drug is an effective analgesic that binds to k receptors. It
does however cause psychomimetic effects, including hallucinations, at higher
doses.
6.3. 4-Arylpiperidines. A series of opiate drugs that helped establish
the minimal structure required for analgesic activity was actually discovered
adventitiously. A compound synthesized in the search for muscle relaxants by
a chemist at the Hoechst laboratories in Germany (24) showed sufficient anti-
spasmodic activity in animal models to be tested for that indication in humans.
The analgesic activity of that compound, meperidine (31) once known as pethi-
dine, was discovered in the course of those trials. The drug quickly found a place
in the clinic because of its good oral activity. This still-widely prescribed opiate,
known more familiarly by the trade name Demerol is approximately one sixth as
potent as morphine. More detailed work showed that the drug was a classic opi-
ate that could be viewed pharmacologically as a version of morphine. This sim-
plified opiate unfortunately had the same propensity to cause addiction as
OPIATE ANALGESICS 13

morphine itself. The much simpler structure compared with morphine led to
intensive work on the preparation of related compounds in many other labora-
tories. It has been estimated that more than 5,000 analogues had been prepared
by 2005 (25). The preponderance of drugs related to meperidine bind almost
exclusively to m receptors. Although this research failed to produce the long
sought after nonaddicting analgesic, it did eventually yield a series of extremely
potent analogues that will be touched on later in this account.

OCH3

N CH3 N CH3
H5C2O 2C
O

Meperidine Ketobemidone
(31) (32)

NH2
N N
H5C2O 2C H5C2O 2C

Pheniridine Anileridine
(33) (34)

Only a very minor portion of the thousands of analogues prepared in indus-


trial and academic laboratories ever reached the market. This research showed
that placing substituents on the benzene ring in meperidine as a general rule
decreases potency. Placing a phenolic hydroxyl group on the benzene ring in
the analogue in which the ester on the quaternary ring carbon is replaced by
an ethyl ketone, which has about the same bulk, gives the analgesic ketobemi-
done (32) (26): an opiate with potency in the same range as morphine. Conflicting
studies indicate that this drug is, or is not, more addictive than morphine. Repla-
cing the methyl group on nitrogen by a longer side chain gives the analgesic
pheneridine (33) (27), a drug that is orally active and about twice as potent as
meperidine. Potency increases again when an amino group is added to the
side-chain benzene ring. The resulting drug, anileridine (34) (28), has been dis-
continued in North America.
The structure-activity relations in this series differ significantly from those
that apply to opiates whose structures retain a larger part of the morphine
skeleton. The congener in which an allyl group replaces the methyl group on
14 OPIATE ANALGESICS

N N
H5C2O 2C H5C2O 2C

Allyl analogue Cyclopropylmethyl analogue

Fig. 7. Analogues.

nitrogen in meperidine for example is an analgesic with potency comparable with


that of the parent compound (29); this derivative, however, does not show any
opiate antagonist activity (Fig. 7). The cyclopropylmethyl derivative acts as a
mixed opiate agonist-antagonist.
Placing methyl groups on the piperidine ring position adjacent to the carbon
that bears the benzene ring changes the overall shape of the molecule as a result
of steric crowding (Fig. 8). The cis isomer in which the new methyl is on the same
side of the piperidine ring as benzene, is some ten times more potent than trans
isomer, the compound in which the methyl and phenyl are on opposite sides of
the ring (30). Molecular models suggest that the preferred configuration of the
cis isomer carries the benzene ring perpendicular to the plane of the piperidine

H5C2O 2C N
CH3
CH3

N CH3
H5C2O 2C
H3C Cis Isomer

N
CH3
N CH3 CH3
H5C2O 2C H5C2O 2C
H3C Trans Isomer

H5C2OCO N
CH3
N
CH3 CH3
CH3
H5C2OCO

Betaprodine Alphaprodine
(35) (36)

Fig. 8. Methyl group addition.


OPIATE ANALGESICS 15

HO HO
HO N CH3
H3C N H3C N
CH3
Nitrogen isomer Allyl Derivative
Picenadol
(37)

Fig. 9. Analgesic activity retained.

because of steric crowding in the alternative configuration. This mimics the con-
figuration of the benzene ring in morphine in which this fragment is locked in
place. The corresponding ring in the trans isomer occupies the expected position
parallel to the plane of the piperidine (30). Much the same is obtained in analge-
sics in which the ester group on the benzene-substituted carbon is reversed so
that oxygen is connected to that atom. Betaprodine (35) in which the methyl
group is on the same side of the cyclohexane ring is some five times more potent
than its isomer alphaprodine (36).
Analgesic activity is retained in the analogue in which the carbethoxy
group is replaced by a three-carbon aliphatic side chain (Fig. 9). That isomer
in which the ring methyl group are on opposite sides of the ring, picenadol
(37), shows approximately the same potency as meperidine or one sixth that of
morphine (31). Although this drug shows good activity in trials in humans, it has
not been commercialized. The analogue in which nitrogen has been moved closer
to the quaternary carbon by one atom retains analgesic activity in animal tests
(32). The N-allyl derivative in this series exhibits no analgesic at all; the com-
pound acts as a pure opiate antagonist again in animal and in vitro assays.
Analgesic activity is retained in ethoheptazine (38), the analogue in which
the size of the heterocyclic ring is enlarged by the insertion of a methylene group
(33) (Fig. 10). The analgesic potency of that congener is approximately one half
that of meperidine. The analogue in which the ring is contracted to a pyrrolidine
shows little if any analgesic activity.
The large intestine ranks second only to the brain as a target organ for
opiates. There, these drugs slow peristaltic contraction to the point where consti-
pation sets in. The aryl-piperidine diphenoxilate (34), with a complex side chain
on nitrogen, was prepared in the course of search for novel opiates diphenoxilate
(39). The compound was at first rated as a failure because it was devoid of

CH3
CH3 N
N

H5C2O 2C H5C2O 2C

Ethoheptazine Ring Contracted Analogue


(38)

Fig. 10. Ring contraction of ethoheptazine.


16 OPIATE ANALGESICS

NC

N
H5C2O 2C

Diphenoxilate
(39)

analgesic activity; the drug did, however, it was noted, retain activity on the gut,
slowing contractions. This agent, under the trade name Lomotil (Pfizer, New
York), was at one time the principal drug for treating traveler’s diarrhea.
6.4. Fentanyl and its Derivatives. The wealth of structure/activity
data available by the end of the 1950s led to the formulation of the so-called
Beckett Casey rule for the chemical structure requirement for central analgesics
(35) (Fig. 11). In brief, that postulate posited that analgesic opiates need to incor-
porate a benzene ring attached to a carbon atom bearing four substituents none
of which is hydrogen, and a tertiary amino group removed at a distance equiva-
lent of a two-carbon chain that originated from the quaternary center. The dis-
covery of the extremely potent synthetic opiate fentanyl (36) raises questions
about that rule because neither of the two benzene rings is attached to a quatern-
ary center. That drug, which is 50 times more potent than morphine in humans
as an analgetic, is still widely used.
The shortcomings of this drug, especially its relatively short duration of
action, spurred further work on analgesics with structures based on the fentanil
motif (Fig. 12). At least five congeners from this program have been evaluated in
clinical trials. Two of these products alfentanyl and sulfentanyl (37) are potent
opiate analgesics currently approved for use in the clinic. Another, carfentanyl
(38), is so potent that its use, like etoprphine, is restricted to knocking down
large animals. The dose required to knock down a moose for example ranges
from 6 to 14 micrograms per kilo. This amounts to about 6 milligrams total
per average moose. It is of note that the benzene ring in these later analogues
of fentanyl is one atom removed from the quaternary center that forms part of
the Becket and Casey postulate.

R
N N N
[ ]
O
R"

Fentanil
(40)

Fig. 11. Beckett & Casy rule.


OPIATE ANALGESICS 17

O O

N N
N N S
O

O O
H3C

Carfentanil Sufentanil
(41) (42)

O O
O
N N CO2CH3
N N N
N O
N N
H O
H3C
O
Alfentanil Remifentanil
(43) (44)

Fig. 12. Structures based on fentanil.

Although these fentanil analogues have relatively short half-lives, situa-


tions may arise when it becomes necessary to cut off drug levels almost immedi-
ately. Replacing the phenylethyl side chain present in carfentanil by a short side
chain terminating in a carboxylic ester gives the congener remifentanil (39). This
ester grouping at the end of the side chain is rapidly hydrolyzed to the
corresponding carboxylic acid by serum esterase enzymes. This in effect almost
immediately drops blood levels of an active drug as soon as administration
ceases. Remaining carboxylic acid from the conversion has no analgesic activity
because that now-polar molecule cannot traverse the blood brain barrier.
6.5. Aminocyclohexyl Series. Several series of compounds that
demonstrate opioid’s analgesic activity in animals carry the basic amine virtually
mandatory for central analgesic activity as an exocyclic group attached to a cyclo-
hexane. It is likely that most of these have never even been tested in humans.
The only marketed representative, tilidine (45) (40), is a relatively potent orally
active analgesic.

H3C CO2CH3
N
H3C

Tilidine
(45)
18 OPIATE ANALGESICS

H3C Cl H3C Cl
N CH3 N CH3
Cl Cl

NH O NH
O O O

Aminoamide Aminoamide acetal


(46) (47)

Cl
N N
Cl
O
NH NH

O O O O

Spiradoline Enadoline
(48) (49)

Fig. 13. Aminocyclohexanes.

The aminoamide (Fig. 13) shows reasonable activity in analgesic tests,


although most congeners display potency in the range of codeine. The potency
of the 3,4-dichlorophenyl analogue (45) is roughly equipotent to morphine (41).
In contrast to the other aminocyclohexanes (Figs. 13 and 14), the structure of tili-
dine conforms to the Becket and Casey rule, whereas that of the aminoamide
does not. Incorporation of a oxygen-containing group on the position opposite
the basic amine results in a six-fold enhancement of potency as an analgesic
(42) (Fig. 13). Two strucurally related compounds in each of which the second
nitrogen atom is however attached directly to the cyclohexane ring bind selec-
tively to k receptors. Spiradoline (48) (43) is a sedative in humans with little
or no analgesic activity. Trials in humans of the close analogue enadoline (44)
were discontinued because of the disphoria caused by the agent.
A sizable series of 1-aminocyclohex-4-one and their 1-aminocyclohex-4-ols
reduction products act as very potent analgesics in the mouse analgesic test
(Fig. 14). Potency increases by decade orders of magnitude when larger groups
are introduced at the position directly across the ring from the amine (45). The
isomer in which the amine and hydroxyl are on opposite sides of the cyclohexane
ring was invariably the more potent than when they were on the same side. The
differential between the pair increased with ascending potency. The most potent
of the series (46), which recreational drug groups have accorded the name broma-
dol, is fully 12,000 times as potent as morphine in mice; the compound binds to opi-
ate receptors at one thirtieth the dose of morphine. On further investigation it was
found that a molecular model of bromadol will overlay a model of fentanil with four
groups, including the basic amines giving a perfect match.
6.6. Open-Chain Analogues. The basic nitrogen in the preponderant
number of synthetic opiates either forms part of a ring or is attached to a
OPIATE ANALGESICS 19

R X

OH
OH
H3C N H3C N
CH3 CH3

Aminoalcohols Bromadol
(50)

Fig. 14. Reduction products.

carbocyclic structure: That functional group is, however, connected to an open


chain of carbon atoms in a small group of central analgesics (Fig. 15). The first
example comprises the still widely used narcotic methadone. This drug was dis-
covered in Germany just prior to World War II in a program intended to find a
substitute for morphine. The drug interacts, almost exclusively, with m opiate
receptors and as a result shows much the same pharmacological properties as
morphine itself. This has led to its very extensive use as a means of maintaining
opiate addicts and sometimes for weaning them from opiates. This usage hinges
on the so-called ‘‘rush’’ that drug abusers get from the sudden rise in blood levels
from injected heroin or morphine. The ready absorption of methadone when
administered by the oral route supports their addiction and allows those indivi-
duals to lead productive lives. Supervised administration of methadone
diminishes the opportunity to hoard tablets for later conversion to an injectable
solution. Such a solution would presumably give the same rush as injected mor-
phine. Many analogues of methadone have been prepared such as hexalgon (47)
in which the amine has been included in a piperidine ring and the methyl on the
nitrogen-containing side chain omitted and phenadoxone (48) with an intact side
chain and nitrogen in a morpholine ring. The pharmacological activities of these,
and many other congeners, are virtually identical with that of methadone.
The motif of a basic amine located at the end of a carbon chain that is in
turn attached to a carbon atom bearing two bulky fragments is followed in
several opioids that have been tested in humans. Ciramadol (51) (49), which
may be viewed as a further simplified congener of methadone is a mixed
agonist–antagonist analgesic agent about twice as potent as morphine. The

O O O
CH3
N N N
CH3 O

Methadone Hexalgon Phenadoxone

Fig. 15. Open chain analogues.


20 OPIATE ANALGESICS

congener, doxpicomine (52) (50), in which the benzene ring is replaced by pyri-
dine and the other ring comprises an oxygen-containing cyclic acetal, displays
about the same potency of codeine. This drug has been characterized as a mild
analgesic that binds to m opiate receptors; it has been used mostly for treating
postoperative pain.

N O

N OH N
H3C CH3 H3C CH3

Ciramandol Doxpicomine
(51) (52)

Replacement of the two bulky groups by a heterocyclic moiety is consistent


with analgesic activity. The drug etonitazine (51) in which a benzimidazole frag-
ment replaces the six-membered rings in ciramandol or doxpicomine is 1,000
times more potent than morphine in animal assay. Clinical trials were disap-
pointing in that the ratio of activity to side effects was if anything more adverse
than that of morphine. Replacement of the bulky groups by a bis-thienyl frag-
ment as in the dithienyl compound (Fig. 16) yields an analgesics with about
the same potency of morphine. Ancillary pharmacological properties mark this
as a classic m central analgesic agent.
As noted, some believe that the route to central analgesics with low abuse
potential and propensity for inducing addiction would involve opiates that act as
mixed agonist-antagonists (Fig. 17). This supposition is borne out by the rela-
tively low incidence of drug dependence among patients exposed to pentazocie
or butorphanol. A relatively simple compound, tramadol, in which a carbon
atom is interposed between the requisite basic amine and a cyclohexyl ring,
seems at first sight to be yet another m opiate. The drug does in fact bind largely
to m opiate receptors. Despite that binding, tramadol does in fact meet the goal of
low tendency for abuse. This may be attributed in part to the fact that that the
drug also acts as a norepinephrin and serotonin reuptake inhibitor, a property

H3C CH3
N H3C N
N
H3C N S
H3C

Etonitazine Dithienyl Compound


(53) (54)

Fig. 16. Replacement of bulky groups.


OPIATE ANALGESICS 21

CH3
HO
H3C HO CH3
N
N
CH3 CH3 CH3

Tramadol Tapentadol
(55) (56)

Fig. 17. Mixed agonist-antagonists.

that is believed to account for the activity of nontricyclic antidepressant agents.


That activity may also account for at least part of the drug’s analgesic action.
This dual activity may be the cause of the relatively low propensity for inducing
drug dependence. The arguably even simpler compound tapentadol was
approved for use in humans as recently as 2008. This drug too shows relatively
weak binding to a m opiate receptor, whereas it inhibits reuptake of norepine-
phrin and serotonin.

7. The Drug Enforcement Agency

One principal activity of the U.S. Drug Enforcement Administration (DEA) com-
prises enforcement of regulation for potentially addictive drugs. One first step in
controlling what they call narcotic drugs involves assignment of the substances
to one of five Schedules. At one extreme of these categories is Schedule I for drugs
such as heroin that have no recognized medical use. Schedule V at the other end
in terms of severity lists such items as cough suppressants that contain a small
amount of codeine. Most opioid analgesics, and the subjects of this review are
consigned to Schedule II drugs. Most constraints are aimed to prevent diversion
of the drugs to nonmedical users or purveyors. Inclusion in Schedule II means
among other things that pharmacies are enjoined to provide the drug only on
presentation of an original prescription signed by a physician who also lists his
DEA registration number; and permits refills only on presentation of a new
valid prescription. Regulations become progressively less stringent for drugs in
Schedules III to V. Those regulations deal in large part with conditions for refills
and record keeping. Some mixed agonist-antagonists are listed in Schedule IV.
It is of interest in this connection that tramdol is not scheduled by the DEA.
The structurally related analgesic tapentadol, however, is listed in Schedule II,
the same group that includes morphine.

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DANIEL LEDNICER
Bethesda, MD

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