TIPS deptember 1983 363

p-Amin&mmcacid 1 Dihydmplertdtns 1 Dihydmiok acid ’ J Lsym- I I 1 Dit-rfdrotolkacid ) I The joint French-US seminar on

Tetrahydroblic acid phencyclidine and related arylcyclohexylamines

Protein syllth8sis A joint French-US seminar was held at La (tram OH/N) one of the most potent opioid Grande Motte (Montpellier) France, 20-24 analgesics known. Removal of the oxygen September 1982, to assess the current sci- group in this series produces compounds entific status of phencyclidine (PCP) and with PCP-like activity to varying degrees. related arylcyclohexylamines. The seminar Zimmerman and associates (Lilly) reported

L______--:-______I was attended by 58 scientists interested in the discovery and characterization of a new Fig. 5. Flow diagram of purim,thymidine and pro- the chemistry, biochemistry, pharmacol- series of benzo(f)isoquinoline derivatives rein synthesis. ogy, therapeutic applications and drug that have stimulus discriminative properties abuse aspects of arylcyclohexylamines. similar to PCP. One of the most potent is problems presented and the management of Thirty-four American, 19 French, 3 Japan the methylcyclopropyl bridged iso research show important differences, it is ese, 1 British and 1 Israeli investigator quinoline, LY 154045. PCP-like effects essential that industry continues to recruit attended, representing each of the above were maximized with a hydroxyl sub its proper proportion of the available talent. major disciplines. The organizing commit- stituent in the aromatic ring. Medawar has commented that the ordi- tee consisted of E. F. Domino of the Uni- One of the major questions in PCP nary processes of scientific discovery are versity of Michigan and P. Geneste and research today is whether there is a PCP slow, messy and uneconomic and cannot be J. M. Kamenka of the Universite de Mont- receptor. Lazdunski, Vincent and col- premeditated. Industry is recognizing that pellier, Ecole Nationale Sup&ieure de leagues (Nice) reviewed the properties ‘creativity and ultimate rewards are sup Chimie. required for a PCP binding site to be called ported by the greatest achievable sophisti- The medicinal chemical aspects were a PCP receptor. These include: (1) cation and fostered by a very tolerant defini- described first. It was shown that many dif- specific, reversible and saturable binding; tion of relevance’ (Hitchings). ferent arylcyclohexylamines possess PCP- (2) a specific correlation between affinity like properties which overlap with the and biological activity such as PCP JULIANH. SHELLEY opioid narcotics. The active conformation stimulus discrimination, mouse rotarod Boehringer lngelheim, Southern Industrial Estate, of PCP was described by Kamenka and behavior etc. ; (3) no displacement of bind- Bracknell, Berkshire, UK. Geneste (Montpellier). Its chameleon-like ing by molecules with a different phar- property of changing the aryl group from macological action; (4) the KD of binding axial to equatorial to the cyclohexyl ring must be in the concentration range for with protonated and non-protonated relevant pharmacological actions; (5) there Reading list molecular species, suggests the complexity must be stereospecificity; (6) tissue re 1 Bindra, J. S. and Lednicer, D. (cds) (1982) Chronicles of drug discovery, Vol. 1, JohnWiley, of determining its active form. This was gional distribution of binding must be con- New York accomplished by studying the effects of sistent with known pharmacological 2 Jamsen, P. A. J. (1971) inD&overies in Biobgi- more thermodynamicahy stable com- actions; (7) a specific antagonist of the cal Psychiatry (Ayd, F. J. andBlackwel1, B., cds), pounds. It was suggested that the biologi- pharmacological effects of PCP must pre- Lippinccot, Philadelphia cally active conformation of PCP requires vent its binding. 3 Hitcbings, G. H. (1976) Design and Achieve- an axial phenyl group in the complex ligand In the case of PCP, most of these criteria, ments in Chemotherapy - A Symposium in receptor. In addition, preferred solution except that of a specific antagonist prevent- honour of G. H. Hitch&s, 31 October 1975, Science and Medical Publishing Co. Inc. conformations, similar to that of PCP ing binding, have been met. Lazdunski 4 Hitcbiigs G. H. (1969) The GHA Clowes hydrochloride, were found for a series of pointed out the maximum binding capacity Memorial Lecture, Cancer Research 29,1895 atylcyclohexylamine hydrochlotides by of PCP of more than 2 pm01 mg-’ protein. Brine and associates (Research Triangle This is a very large amount of binding as Institute). Lednicer (Adria) and P. F. Von compared with the binding capacities for Voigtlander (Upjohn) described the most neurotransmitters. Pronase, trypsin chemistry and structure-activity relation- and papain treatment destroys PCP bind- ships of a series of 4-aminc&arylcyclo- ing, but phospholipases do not. This, and hexanols. The presence of an oxygen the stereospecificity of the binding, show function on the cyclohexane ring produces that the receptor is a protein. High Na+ compounds that are narcotic opioids, both concentration blocks PCP binding, as do pure pagonists and mixed pagonists local anesthetics and histrionicotoxin. PCP antagonists, as well as pure kantagonists. also acts on the muscarinic cholinergic The bromo, phenethyl derivative (U 48843) receptor, but at high concentrations near 30 has 12 300 times the potency of morphine PM. In embryonic chick cardiac cells in cul- as an analgesic of the ktype. This makes ture, PCP produces a negative inotropic this compound, 4-@ bromophenyl&4- effect just like acetylcholine (ACh). In (dimethylamino) - 1 - phenethylcyclohexanol neuroblastoma cells in culture PCP blocks 364 TIPS -September 1983

the Na+-channel and the K+-channel. The increase dopamine release in similar assays and Domino (Michigan) described a new K+-channel is completely blocked when but at higher doses. major route of phencyclidine biotransfor- PCP reduces the Na+-channel activity by M. E. and A. T. Eldefrawi (Maryland) mation via hydroxylation at the 3 position 50%, causing a reduced, but prolonged pointed out that [SHIPCP binds to allosteric of the cyclohexyl ring and subsequent for- action potential. The Ca’+-dependent sites on the ACh receptor of the torpedo mation of dihydroxylated derivatives, 3,4- K+-channel and the slow Caz+-charmel are electric organ and to proteins in crayfish dihydroxycyclo PCP and 3-hydmxycyclo- not affected. PCP also blocks dopamine abdominal muscle membranes. The latter 4-hydroxy-pip PCP in mouse, monkey and (DA) uptake in concentrations which are binding is particularly sensitive to divalent human. This pathway is deficient in certain the same as those found for the saturation of cations, which inhibit Ca*+ channels. The inbred strains of mice and is completely the PCP receptor with [SHIPCP. From a rank-order of several PCP analogs in dis- undetectable in the rabbit. In general structure-activity point of view, metu placing [SH]PCP binding to crayfish protein alicyclic hydroxylations occur preferen- OH-PCP (a potential PCP metabolite) is the correlates better with their inhibition of tially over aromatic hydroxylations. The 3- most potent of the compounds studied; it is [8H]PCP binding to rat brain than to the tor- and Cpositions on the cyclohexyl ring and also very potent in its affinity for opiate pedo ACh receptor. Although PCP actions the Qposition on the piperidine are prefer- receptors. on the Caz+ channel are implicated, red sites of PCP oxidation. Hydroxylation S. R. Zukin (Albert Einstein College) Albuquerque of the same University could of the aromatic ring of PCP, if any, occurs reviewed recent progress in PCP receptor find no direct effects of PCP on the Ca’+ only in trace amounts. Each hydroxylation research. He further characterized its kin- channel of the frog neuromuscular junc- of PCP on the alicyclic ring is probably etic association and dissociation rate con- tion. mediated via a different form of cyto- stants as 2.9 x loshl-’ and 4.8 x Due to illness, neither Maayani nor chrome P450, as suggested by differential 10-l min-‘, yielding a KD of 1.6 x ~O+M Weinstein (Mount Sinai) was able to abundance and inducibility of each path- in agreement with previous data. The per- attend the seminar. The abstract of their way in various mouse strains. On the basis missible separation time of 13 s was well paper covered the discriminant strut of experiments with inbred strains of mice, above the 10 s of the rapid filtration assay. ture-activity relations of PCP and its it was concluded that the hydroxylations of Precoating the filters with 0.01% poly-L derivatives, as well as the multiple phar- PCP on alicyclic rings are mediated by lysine or 0.05% polyethyleneimine elimi- macological actions of PCP in which its cytochrome P450 forms different from nated any displaceable [sH]PCP binding to actions on the muscarinic cholinergic recep those associated with aryl hydrocarbon GF/B filters. Stereospecificity for the PCP tor as well as on K+ channels in cardiac hydroxylase activity. Trevor and his col- receptor was demonstrated in that (+ b muscle were studied. In spite of the absence leagues (University of California, San ketamine was four times more potent than of these investigators, the round table dis. Francisco) reported on the remarkable (-~ketamine, and dexoxadrol was 100 cussion chaired by Vincent brought out stereoselective biotransformation of the times more potent than levoxadrol. Pro some heated discussion, in which the enantiomers of ketamine by the liver of rats teolytic enzymes, including trypsin, papain majority felt that the evidence for a distinct and human heart transplant donors. Marked and thermolysin, inactivated stereospecitic PCP receptor was considerable, and that the stereoselectivity was observed in alicyclic and overall specific PCP binding. The sub problem of the rapid filtration assay raised ring hydroxylation in rat hepatic micro- icular cortex and hippocampus showed the by the Weinstein group had now been somes in contrast to that from humans. The greatest PCP binding, with intermediate resolved. All lamented the lack of a specific major hydroxylated metabolites formed levels in the frontal cortex, hypothalamus, PCP antagonist and its need in further PCP from both ketamine enantiomers by human cerebellum and striatum. Negligible levels receptor studies. liver microsomes were Qhydroxyketamine of PCP binding were found in the white The biotransformation of the piperidine and 6hydroxynorketamine. matter of the corpus callosum. ring of PCP was described by Cho and An overview of the human behavioral R. S. Zukin (Albert Einstein College) Kammerer and colleagues (University of psychopharmacology of the arylcyclo reviewed the biochemical evidence for a California, Los Angeles). They used rat hexylamines was provided by Gallant common PCP/cr opiate receptor. She and rabbit 9 000 x g liver supematant to (Tulane). PCP is a positive reinforcer in stressed that it is not an opiate receptor, but show the conversion of PCP to (l- animals and, presumably, in man because it rather a unique and distinctive receptor. phenylcyclohexyl)-1,2,3,4tetrahydropyti- is abused extensively. A rather high inci- According to this concept, Zajac, dine, a possible decomposition product of dence of PCP intoxication was observed in Roques and colleagues (Universite Rene the corresponding carbinolamine. The N- patients treated in the New Orleans Charity Descartes) showed that highly selective oxide of PCP was not an important inter- Hospital Emergency Room. Marked and synthetic peptides with brain CL_ and mediate. Their data indicated that 5-[N- confusing mental and neurologic sympto &opiate receptor agonist actions did not (1 ‘-phenylcyclohexylkunino] pentanoic matology was observed in these patients. interact with PCP binding sites. Indeed, acid and N- (5hydroxypentyl> l-phenyl- Gallant stressed the fact that the lipophilic these agonists exhibited low inhibitory cyclohexylamine are formed from the car- nature of PCP and the prolonged clinical potency (I& 10 000 no) on [3H]PCP binolamine of PCP or its open ring form, course of psychotic behavior in some binding in rat brain. g-selective agonists through oxidation or reduction by soluble patients may be associated with a slow rate increased [3H]DA release in vivo after liver enzymes. Kalir (Tel-Aviv) and Trevor of PCP excretion in the urine. For example, intracerebroventricular injection in caudate (University of California, San Francisco) human urines can be positive for PCP as nucleus of cats and in vitro in rat striatal and colleagues reported on the formation of long as 30 days after the last exposure, with slices. This effect, which is not antagonized an iminium ion of PCP. The metabolically positive urines averaging 2 weeks after the by naloxone, was obtained at low doses and dependent covalent binding of [sH]PCP to last use of PCP. Aniline, Pitts and asscr may be related to the behavioral effects of microsomal proteins was inhibited by ciates (University of Southern California) opiates. Interestingly, PCP was also cyanide ions, suggesting that the interaction stressed the serious nature of PCP abuse in reported by Howard-Butcher (University of of their iminium derivative of PCP could patients at Los Angeles County Hospital. California, Los Angeles) and Johnson explain the long term, and irreversible bind- They emphasized that epidemiological (University of Texas, Galveston), to ing of PCP to cellular proteins. Holsztynska studies on the prevalence of PCP abuse TIPS September 1983 365 must be based upon highly sensitive and the consequences of extensive acidification active from inactive PCP analogues based specific methods of PCP analyses in blood techniques during PCP intoxication. on the interaction of the compounds with or urine, especially using modem gas Only 80% of the total dose of [SHIPCP ionic channels of electrically excitable chromatographic-mass spectrometric could be accounted for, based on urinary (c. membranes and cholinergic receptors. An methods for detecting not only PCP but also 60%) and fecal (c. 20%) excretion. About important correlation was made between its related congeners of abuse. Lack of suit- 1% of the dose of PCP is excreted in the dog the ability of PCP and its derivatives to able and sophisticated analytical methods to as free PCP in the urine, with various block K+- and Na+-channel inactivation measure these substances may lead to false metabolites, especially the aminopentanoic rather than affect the recognition sites of assumptions in surveys reporting, for in- acid derivative (14.7%). Woods ‘cholinergic receptors. stance, decreased use of PCP, while street (Michigan) reported on drug modification Palmer, Hoffer and associates (Col- use may involve smaller dosage of PCP and of PCP discriminative performance in orado) described the remarkable properties a shift to the use of its congeners. pigeons and rhesus monkeys. The data of PCP and related derivatives on the While PCP is a major drug of abuse in the indicate a unique nature of PCP discrimina- release of norepinephrine (NE) from the rat USA, Ingold (Centre Medical Marmottan) tive cues, which are shared by related aryl- cerebellum and hippocampus. These inves pointed out that PCP is not abused in France cyclohe.xylamines as well as certain benzo tigators used electrophysiological methods, at this time. He suggested that its abuse in motphans and homobenzomorphans. together with micropressure ejection from the USA is due to its general availability. Haloperidol, diazepam and l-phenyliso- multibanelled micropipettes, to show that Why do people use PCP? Ingold suggested propyladenosine, in doses sufficient to alter PCP mimicked the actions of NE on single its unique pharmacological properties of performance, failed to alter the discrimina unit activity, with ketamine being about l/5 euphoria, amnesia and anesthesia; group tive control of PCP. Important species dif- as potent. PCP no longer exerted its de pressure to accept a risk, and PCP negative, ferences to different drug classes were also pressant actions on cerebellar Purkinje cells as well as positive reinforcing properties to noted. following lesions of the NE innervation to induce a change of mental state, are all Shannon (US National Institute on Drug cerebellum with 6-OH dopamine, intenup involved. PCP induces a unique state of dis- Abuse) reported on the structure-activity tion of presynaptic NE release by local tortion of body image, akin to a phantom relationships for producing arylcyclohexyl- Mg.+ applications, or NE depletion by, limb syndrome. aminelike behavioral effects in rats. In reserpine administration. These data sug- Braude (US National Institute on Drug contrast with other investigators who use gest a presynaptic effect of PCP on NE Abuse) provided an overview of the NIDA food reinforcement in discriminative release. The effect of PCP on hippocampal biomedical program on PCP and metabo stimulus studies, he used shock avoidance neurons was more complex, but consistent lites. Due to the epidemic of PCP abuse in in rats. This facilitated the use of larger with a presynaptic mechanism of action at the USA, beginning in 1979 NIDA funded doses of these agents in determining their monoamine synapses. Higher doses caused about 40 projects and contracts on PCP in behavioral effects. Systematic strut local anesthetic effects in both brain areas. relation to other drugs of abuse, of which 17 tune-activity studies allowed Shannon and The expected stereospecific potency differ- projects were on PCP alone. Reduced his colleagues to define the properties of the ences of PCP analogues were also availability of funds and reassessment of PCP receptor, including an anionic site described. NIDA priorities will undoubtedly bring which binds the protonated nitrogen, two Lodge and associates (Royal Veterinary PCP research to a lower level in the future. opposing n aromatic sites and an inter- College, London) pointed out that the aryl- In view of the scientific and public interest mediate lipophilic area. cyclohexylamines selectively reduce exci- in PCP, the majority of participants felt this Stiller and colleagues (Pittsburgh) tation of cat central neurons by aspartate was most regrettable. reported on the developmental aspects of like amino acids. They used the technique Balster and Wessinger (Virginia) the human clinical pharmacokinetics of of microiontophoresis and studied reviewed their extensive research on the ketamine. Their data, using cardiac ketamine in particular. Ketamine reversibly CNS depressant effects of PCP. Although patients, were surprisingly consistent with reduced the excitation of spinal cord PCP and other arylcyclohexylamines pro- other reports in the literature in which neurons by N-methylaspartate to a greater duce a unique type of general anesthesia, ketamine has a short t 112o-phase of about 10 extent than that of either kainate or quis- PCP has many pharmacological and min and a much longer t rn pphase of about qualate. The (+ ~enantiomer of ketamine behavioral effects similar to typical CNS 120 min. Some unique data in infants, chil- was 3X as potent as its (-)-isomer as an depressants, such as the barbiturates. These dren and pregnant females during labor N-methylaspattate antagonist, and only 1 include the phenomena of tolerance and were also described. Ketamine t I/ZPphase to 1.5x as potent as an ACh antagonist. dependence. PCP also markedly enhances was faster (55 min) in children (l-5 yr) and Ketamine had no effect on GABA- the depressant effects of barbiturates. slower (185 mm) in infants (2-10 m) than mediated transmission in contrast to bar- Mayersohn and associates (Arizona) adults. The hemodilution effects of cardiac biturates which potentiated it. reported on PCP disposition kinetics in bypass (CBP) altered the &phase in all Howard-Butcher showed that there was dogs. They developed a radioimmunoassay patients, but resumed a log-linear concen- an inn-viva release of dopamine (DA) in the for PCP, and a capillary column gas tration curve after CBP was concluded. cat caudate nucleus after PCP administra chromatographic method using nitrogen Ketamine plasma protein binding levels tion using the technique of cyclic vol- detection for a number of its metabolites. were elevated in all patients except in the tametry. In addition she showed that PCP In dogs, PCP has an extremely large vol- cord blood, w,here they were l/3 to l/2 affected ACh turnover consistently with its ume of distribution indicating extensive dis- those of the mother. These investigators effects on DA release in the striatum. tribution to tissues. Systemic clearance of also showed that increasing the blood pH Murray (Washington State University) and PCP was large, and approached the value of increased ketamine binding, as is true for his colleagues (NIMH at St. Elizabeth’s hepatic blood flow. PCP is poorly bound to PCP. Emory University supplied some of Hospital) compared the effects of PCP with serum proteins with dependence on pH. the patient samples. those of other psychoactive drugs on Binding of PCP increases with pH. This Albuquerque and associates reported on cholinergic dynamics in the rat brain. Sub raises an interesting question as to what are the ability to differentiate behaviorally anesthetic doses of PCP and ketamine 366 TIPS -September 1983 increased ACh turnover in the neocortex differences of PCP in rats. Female rats were resent the a-opioid receptor. Two other and diencephalon, but had no effect on more sensitive to the diverse effects of PCP sites of high affinity for ethytketccyc striatal and hippocampal ACh. This reg- than males. The enhanced sensitivity of lazocine not affected by PCP may represent ional brain pattern of ACh turnover induced females compared with males was related K-opioid or benzomorphan sites. by PCP was similar to that of cocaine, but to a higher brain content of PCP and more Kamenka, Geneste and coworkers demon- was completely different from other classes prolonged brain and plasma half-lives in the strated by ‘YLNMR spectroscopy that the of centrally acting drugs. females. The content of hepatic micro stereoisomers in the 4-aryl-Qpiperidino- l- Johnson reported that PCP affects DA somal cytochrome P450 was also found to phenethyl cyclohexanol series of hydro- and ACh release from rat striatal slices in be lower in the female rats. chloride salts are easily distinguishable by vitro. PCP increased the spontaneous Fukuda and Domino (Michigan) corn the chemical shifts of the methylene group release of DA but had no effect on K+ pared the EEG and gross behavioral effects OLto the cyclohexane ring. stimulated [8H]DA release. His results sug- of various dissociative, general and local Rondoin, Baldy-Moulinier and asso- gest that PCP releases [SH]DA in a manner anesthetics in Macuca mulutta. They con- ciates (Montpelher) have mcorded cortical similar to nonamphetamine stimulants. cluded that PCP, ketamine, dexoxadrol and and hippocampal EEG activity in chronic PCP can release both stored and newly dextrorphan had similar EEG and gross rats. PCP (2-5 mg kg-‘), or its active synthesized DA, which serves to down reg- behavioral effects in contrast to the other analogues, produced awake EEG activity ulate DA synthesis. At similar concentra- centrally active agents studied. Their fmd- associated with locomotor stimulation dur- tions (3-30 pM) PCP inhibited potassium ings are consistent with the data obtained ing the fit hour following i.p. injection. stimulated release of [8H]ACh, while from stimulus discrimination and PCP Slow wave sleep and, finally, paradoxical atropine had no effect. Oxotremorine, a receptor binding studies. sleep reappeared later. No changes in muscarinic cholinergic agonist, also inhi- Vaupel (US National Institute on Drug &activity were observed. Levine (Univer- bited [sH]ACh release and in combination Abuse) reported on the effects of PCP in the sity of California, Los Angeles) reported with PCP the effect was additive, suggest- chronic spinal dog. The pharmacology of that chronic PCP treatment in doses of l-2 ing that the atropinelike properties of PCP PCP, its similarity to SKF 10047 and the mg kg-’ produced marked behavioral ate unimportant in this paradigm. The profiles of eight PCP analogues abused by effects in developing kittens. He compared (+ )-enantiomer of SKF 10047 but not the man were studied. He concluded that the the effects of chronic low doses of PCP with (- ~enantiomer also inhibited [SH]ACh chronic spinal dog was an excellent model single larger doses of PCP, two of its release. This effect was blocked by in which to study PCP derivatives and metabolites, I-phenylcyclohexylamine, N- haloperidol, just as with PCP. Hence, PCP obtain their behavioral, neurologic and (5 - hydroxypentyl) - 1 - phenylcyclohexyl- and (+ >SKF 10047 may stimulate DA physiologic profiles. The structure-activity amine, and the PCP analog N,N-diethyl- release via a PCP/o-receptor action. relationships of various PCP derivatives I-cyclohexylamine. The most intense PCP Castellani (Wichita) reported on the were in the expected direction, with PCP induced motor responses in kittens 30-50 complex role of dopaminergic, cholinergic and SKF 10047 showing very similar days of age, consisted of waxy rigidity. The and opioid agonists and antagonists on vari- pharmacological profiles. Von Voigtlander N,N-diethyl analog produced less intense ous aspects of PCP induced behavior in and Tang (Upjohn) reported on an exten- effects. The two PCP metabolites were less rats. His data were consistent with PCP sive search for PCP antagonists. Although active, with the alcohol derivative being the induced release of DA and its partial block- no specific antagonists were found, prazo least potent. ade by haloperidol in both rat and man. sin and clonidine were noted to block a Lozovsky, Kopin and associates (US None of the transmitter agonists or antagon number of the effects of PCP in various National Institutes of Health) reported that ists alone reversed all of the complex behavioral studies. This suggests an import- PCP caused a rapid dosedependent sup behavioral effects of PCP, because all three ant role for the a-adrenergic system in the ’ pression of plasma prolactin in rats. Toler- brain transmitters seemed to be involved. mediation of some of the actions of PCP. ance to this effect was observed following Browne and Welch (Pfizer) added adeno Quirion and Pert (US National Institute of daily PCP for 28 days. They also showed sine to the list of putative nemotmnsmitters Mental Health) reported on the histochemi- that chronic PCP caused an 18% decrease involved with PCP effects. They obtained cal localization of PCP receptors in the rat in the B, for [8H]spiperone bmding with data in rats showing that various adenosine brain. PCP binding was especially high in no change in the KD. Thus, a decrease in agonists completely antagonized the dis the hippocampus and neocortex. They also DA receptors might be responsible for the criminative stimulus effects of PCP in vivo showed that D&receptors, as measured by observed tolerance to the acute suppressive and blocked the high, but not the low, affii- labelled spiperone, decreased with chronic effect of PCP on plasma prolactin. How- ity receptor of [SH]N&cyclohexyladeno PCP administration in a manner consistent ever, there was no tolerance to the sine in vitro. Nabeshima and Kameyama with PCP induced DA release or blockade locomotor stimulant effects following 28 (Meijo) studied the actions of acute and of DA uptake. Especially exciting was their days of PCP administration in rats.. The chronic PCP administration on Met- report of the isolation of a peptide substance (+&isomer of 1-( I-phenylcyclohexylb enkephabn in the mouse brain. A complex of small molecular weight which was a 3-methylpiperidine was more potent in picture was produced by PCP, in which potent endogenous ligand of the PCP recep reducing plasma prolactin than its (- )- there. was a lowering of Met-enkephalin in tor. They named this peptide ‘angeldus isomer. Their study suggested a PCP agon the medulla and midbrain but no change in tine’. The finding of endogenous peptides ist action on the DA system to which toler- the striatum, hippocampus and neocottex. that displace PCP from its receptor was also ance can develop, but also a more complex After development of tolerance to PCP, an reported by Vincent and associates and the effect on locomotor activity. increase in Met-enkephalin levels was zukins. It was concluded after four days of inten observed in the striatum. However, during Morre and associates (Sanofi) used sive presentations and discussions that PCP morphine withdrawal in PCP tolerant mice, guinea-pig brain membranes,to show that and related arylcyclohexylamines are a the increase in Met-enkephalin levels PCP displaces [8H]ethylketocyclazocine very rich and fertile subject of research that returned close to the control levels. These from its low affinity binding site. This site, can lead to a better understanding of investigators also reported important sex which is insensitive to naloxone, may rep neurobiology, and possibly new therapeu- . TIPS - Jeptember 1983 367

tic agents, particularly in the form of still remaining unanswered after the meet- EDWARD F. DOMINO ultrashort acting anesthetics and analgesics ing was why are there PCP receptors and Department of Phamacology, University of with less respiratory depression. Such short related endogenous peptide ligands in the Michigan, Ann Arbor, MI 48109, USA. acting agents would probably be less brain? For what purpose? Are-they there to JEAN-MARC KAMFiNKA AND abused than longer acting compounds like produce a dissociated mental state follow- PATRICKGENESTE PCP itself, with metabolites that irrevers ing severe trauma or stress? Universire de Montpellier, Ecok! Nationale, ibly bind to proteins. The ultimate question Sup&ieure de Chink, Montpellier, France.

Current awareness series

Key developments in pharmacology

Conformation-activity study of The relatively small energy difference between the axial and equatorial phenyl 4=phenylpiperidine analgesics conformers of I and II suggests that in solu- In the light of the original hypothesis’ that tive Configuration Interaction using Local- tion there should be an appreciable popula- analgesic 4phenylpiperidines should have ized Orbitals). Owing to its speed, this tion of phenyl axial conformers present. their phenyl ring in an axial position on the method of calculating empirical potential This would make the structure-activity piperidine ring, in analogy with the rigid functions allows the user to minimize a relationships of I and II more similar to the polycyclic analgesics such as morphine, it structure with respect to all internal co- rigid Cphenyl axial morphmomimetics, is rather puzzling to note that over the years ordinates (bond lengths, bond angles and such as morphine, where the introduction an impressive amount of experimental data torsion angles). of a meta hydroxy group is known to en- has accumulated which shows, almost Phenyl equatorial conformations were hance potency. A similar effect of the meta without exception, that the phenyl ring is in found to be preferred for I and II over the hydroxy group is known for I and II. The an equatorial position. In fact, X-my cry- phenyl axial conformation by only 0.6 and fact that a meta hydroxy group has a detri- stallographic analysis, nuclear magnetic 0.7 Kcal mole-’ respectively. The energy mental effect on the analgesic activity of the resonance data and quantum chemical cal- differences between the phenyl equatorial prodines is in accord with the present calcu- culations indicate that compounds structur- and axial conformers were calculated to be. lations indicating that the phenyl axial con- ally related to pethidine and prodines, have 1.9, 2.8 and 3.4 Kcal mole-’ in favour of formation populations are virtually non- their phenyl rings in an equatorial position the phenyl equatorial conformers for existent. It is noted, however, that I and II on the piperidine ring. 3-demethylprodine, (Y- and Pprodine are still different from the rigid Cphenyl The fact that the various diastereoiscr (III, IV) mspectively. A phenyl axial con axial morphinomimetics, since N-ally1 mers of prodines and prodine-like anal- former was calculated to be preferred by groups do not convert them into antagon- gesics show marked enantiomeric and 0.7 Kcal mole-’ for the 3-demethyl deriva- ists. diastereoisomeric potency differences, tive of V whereas the phenyl equatorial Whether the phenyl axial conformation make these compounds extremely valuable conformers were preferred by 1.3 and 3.3 is intimately connected with the presence of for gaining a better understanding of recep Kcal mole-’ for the OL-and /3-compounds a meta hydroxy group is, however, still not tor and receptor-induced events. As the W). settled, owing to the observation that question of axial v. equatorial phenyl has The results clearly show that the equilib- phenylmorphans contain a meta- not yet been satisfactorily settled, rium distribution of phenyl equatoriaLaxial hydroxylated phenyl in a fixed equatorial Froimowitz’ addressed the problem of the is quite variable, and depends on the nature position. energy differences between phenyl equator- of the substituent on the Cposition and the The present study of Froimowitz clearly ial and phenyl axial conformers in various presence or absence of a substituent in the suggests that a 3-methyl substituent on the Cphenylpiperidine analgesics. 3position. piperidine ring strongly governs the prefer- The conformational energy of pethidine COOC2H5 I)COC2H5 I, ketobemidone II, cY-prodine III, yOCP5 fi-prodine IV and 1,3,4 - trimethyl - 4 - I phenylpipetidines V was studied using the MM2 (Molecular Mechanics Il) program developed by Alhnger and coworker?. The MM2 program is based on forcefield cal- culations, and therefore offers the distinct advantage of speed of calculation over even the fastest semi-empirical quantum chemi- cal calculation, such as PCILO (Perturba-