STRUCTURE-ACTIVITY-RELATIONSHIPS FOR MECAMYLAMINES ANTAGONISM OF NICOTINE IN THE CENTRAL-NERVOUS-SYSTEM

Although mecamylamine antagonizes many of nicotine's effects in the ce ntral nervous system (CNS), the mechanism by which this antagonism occ urs is not yet fully understood. We studied the in vivo responses of v arious mecamylamine analogs to determine the existence of structure-ac tivity relationships. Doses which produced 50% antagonism (AD(50)) in the presence of an ED(84) of nicotine were calculated for the analogs in both the tail-flick and spontaneous activity tests. It was found th at the amine position yields optimal in vivo activity when joined to a single methyl substituent, as is the case with mecamylamine; the addi tion of larger substituents decreases activity. This was especially tr ue in the case of the tail-flick test. N-Benzyl mecamylamine displays poor antagonist activity while N-(4-fluoro) and N-(4-nitrobenzyl) meca mylamine seem totally inactive. Furthermore, [H-3]nicotine binding was not displaced in vine by mecamylamine analogs. Based on pharmacologic al data such as this, it appears that mecamylamine's mechanism of acti on in the CNS is distinct from that of nicotine and may not be mediate d by the same population of receptors to which nicotine binds.