Tobacco Documents Online

1 SUMMARY The recently discovered nicotinic agonist pyrido[3,4-b]homotropane (PHT) as well as its N-methyl and 21-methyl derivatives (syntheses reported herein) were compared with nicotine, nor-nicotine and anatoxin-a in a series of in vitro and in vivo assays encompassing both central and peripheral effects. The results reveal that PHT possesses activity equal to that of the highly potent agonist anatoxin-a. The relative inactivity, both in vitro and in vivo, of N-methyl and 2'-Me-PHT supplies additional information on the structure-activity requirements of conformationally restricted nicotinoids.

5 by prostration in rats, correlated well with the relative affinity of ['H]-nicotine (Table 3). With [3H]-MCC as the ligand, the binding affinity as well as their rank order was similar to that observed with [=H]-nicotine with a few exceptions: the affinity of both PHT and anatoxin-a was 100-fold greater for Tor edo than for rat brain membranes (Table 2). Furthermore, the affinity of both agents for Torpedo membranes with ['H]-MCC as the ligand was 10-fold greater than that for nicotine; and the IC50 values were 10-fold less than those obtained with [=H]-nicotine as the ligand. This difference in the affi- nities of the nicotinoids for Torpedo and rat brain membranes may be a reflec- tion of the differential nature of the nicotinic receptors; while their differences in relative affinities with the two radioligands is indicative of the more complex nature of the recognitioin sites for nicotine as compared to acetylcholine or MCC.5 Although 2'-Me PHT (3b) places a methyl in about the same position as the acetyl methyl of s-cis anatoxin-a (4a) its activity was greatly diminished compared to PHT (3a). It is possible that the rigidly planar pyridine of 3b, in contrast to the flexible enone of anatoxin-a, is unable to avoid energeti- cally unfavorable steric interactions arising from the presence of the added methyl. Methylation of pyridohomotropane on nitrogen to give 3c also resulted in a considerable loss of activity. The analogous methylation of nornicotine, on the other hand, produces a compound (nicotine) which has ten times the activity of the secondary amine`. It is likely that the tertiary amine (3c) is not sufficiently accessible to the site of negative charge at the receptor because of the addition of the 2-carbon bridge and its protons. N ~ Conclusion ~ ~ ~ ~ ~ ~