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The Joint French-US Seminar on Phencyclidine and Related 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
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  • Introduced B.,Byhansen, 16
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