Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice

Abstract

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP, I) and many of its analogues have shown some pharmacological effects. In this study, new pyrrole derivatives of I (1-(1-phenylcyclohexyl)pyrrole, II and 1-[1-(4-methylphenyl)(cyclohexyl)]pyrrole, III) and their intermediates were synthesized and the acute and chronic pains were examined on mice using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests and the results were compared with the PCP and control groups. The results indicated that III generated higher analgesic effects in the tail immersion test compared to the PCP and control (dimethyl sulfoxide, DMSO) groups, demonstrating a marked and significant increase in tail immersion latency, but this effect was not observed for II in the dose of 1 mg/kg. The formalin test showed that III was effective in acute chemical pain (phase I, 0-5 min after injection), but was not effective for II at the same dosage compared to the PCP and control groups. Also chronic pain will be significantly attenuated by III but II was not effective as compared to the other groups. It is concluded that substitution of the aromatic pyrrole ring instead of piperidine in the PCP molecule will not be effective alone in tail immersion and formalin tests but the addition of a methyl group (with high electron donating and dipole moments) on the phenyl group plus substitution of the aromatic pyrrole ring can be effective in acute and chronic pain compared to the PCP and control groups.

The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

“…Other publications have described a variety of other synthetic analogues of ketamine and PCP, so it is likely that many other chemical analogues of this family of drugs will be found to possess the characteristic dissociative anaesthetic properties of ketamine and PCP [18], [23], [24], [25] [26]. These results imply that abuse of these ketamine and PCP analogues could be associated with significant psychiatric sequelae.…”

Pyrrole analogues of Phencyclidine decrease food and water consumption in mice

“…As indicated in our pre vious work on substitution of methyl group (high elec tron donating group with more electron distribution and dipole moment), methylphenyl (tolyl), instead of phenyl group, generates stronger analgesic effects [13].…”

“…In such condition, the non bond ing nitrogen electrons of piperidine are free and this atom will contribute to hydrophilic properties more than pyrrole. Moreover, strong electron donating properties of the methyl group on the para position of the phenyl ring (III) increased behavioral effects of the new derivatives [13,38,39].…”

“…Finally, this compound was pre pared from 1 pyrrolecyclohexanecarbonitrile (V) and 4 methylphenyl magnesium bromide according to a known procedure. The hydrochloride salt of II was prepared using 2 propanol and HCl and was recrystal lized from 2 propanol [13] scheme.…”

“…Previous studies demonstrated that PCP and its analogues alter food and water intake in deprived and non deprived animals [11,12]. Because of some phar macological properties of Pyrrole derivatives and effective physiologic activity of these analogues of PCP [13], in the present study, effects of the new pyr role derivatives of PCP on food and water intakes were evaluated.…”