Structure-activity relationships of arylcyclohexylamines as discriminative stimuli in pigeons

The effects of a variety of arylcyclohexylamines, opioid drugs and other drugs were studied for phencyclidine-like effects in pigeons trained to discriminate phencyclidine (PCP) from saline. There was a good correlation between the relative potency of arylcyclohexylamines as PCP-like discriminative stimuli in pigeons and these drugs as discriminative stimuli in rats. Substitution of methyl groups on the piperidine or cyclohexyl rings of PCP reduced potency, but not efficacy, whereas substitution of hydroxyl groups decreased both potency and efficacy. Replacement of the phenyl ring with a thienyl ring increased PCP-like activity, but replacement of the piperidine ring with a pyrrolidine ring or a morpholine ring decreased potency. Compounds with methyl or ethyl groups on the nitrogen atom replacing the piperidine ring also were active. These data suggest that N-alkyl substitutions decrease potency but not efficacy, whereas hydroxylation of the cyclohexyl ring decreases efficacy as well. The data also support the suggestion that size of the aromatic ring is also a determinant of PCP-like activity. Both optical isomers of cyclazocine and N-allylnormetazocine were active as PCP-like discriminative stimuli, although the (-)-isomer was more potent than the (+)-isomer for cyclazocine and the reverse was true for N-allylnormetazocine. The pigeon shows less stereospecific activity with these drugs than the rat and especially the squirrel monkey. A variety of other opioid-like chemical structures, as well as other drugs such as d-amphetamine and pentobarbital, were inactive as PCP-like discriminative stimuli.