| Phencyclidine and seven phencyclidine analogues were synthesized and tested biologically as possible antagonists towards phencyclidine (PCP). The analogues possessed alkyl substituents instead of a cyclohexyl ring and are known as N-benzylpiperidines. The syntheses were accomplished by either a two step reaction, the first step being the formation of a nitrile intermediate and the second the conversion to final product by a Grignard reaction or by a substitution reaction between piperidine and N-benyzlbromide. The compounds were purified by column chromatography, distillations, triturations under petroleum ether and by repeated recrystallizations. Verifications of purity were accomplished by melting point determinations, thin layer chromatography and gas-liquid chromatography. Structural verifications were performed by nuclear magnetic resonance spectroscopy and mass spectroscopy. Infrared and ultraviolet spectroscopy were also performed for characterizing these compounds.; Biological characterizations were performed on the N-benzylpiperidines and PCP. Median lethal doses (LD-50's) were determined by injecting a geometrically increasing dosage of test compound into a set of 4 mice until death was induced in all 4 mice. Median effective doses were calculated by a forced motor activity study using a rotarod apparatus (which essentially measures ataxia). After training the mice to be able to remain on the rotarod for 2 minutes, a known amount of test substance was injected intraperitoneally and the mice were again tested for the ability to remain on the rotarod. Testing began 5 minutes post injection and continued every 5 minutes until the mouse could remain on the rotarod for 2 minutes or 1 hour had elapsed. Linear regression analyses were performed on at least 3 dosage levels which induced some measurable ataxia. The time interval was used which demonstrated maximal measurable ataxia. Antagonism studies were performed with a rotarod apparatus to determine if a given dosage of analogue could raise the predetermined ED-50 of PCP. The antagonism studies began with the simultaneous injection of the ED-50 of PCP and a given amount of analogue. An increase in ED-50 of PCP would imply that the compound was antagonistic to the intoxicating effects of PCP as measured by rotarod. Unfortunately none of the compounds proved to be antagonistic toward PCP. |
