Selectivity of sterically fixed tryptamine and 5-methoxytryptamine derivatives for serotonin receptor subtypes, II: Structure-activity relationships and in vitro pharmacology of N-alkyl- and N,N-dialkyl-3- indolylbicyclo-[2.2.1]-heptane-2-amines.

Twenty-four norbornane analogues of tryptamine and 5-methoxytryptamine were investigated for affinity at 5-HT2 receptors of the rat tail artery and proved to be weak non-competitive antagonists of 5-HT. Compound 12 which displayed a marked depression of the concentration-effect curves, was examined for potential interaction with the allosteric binding site of the 5-HT2 receptor. The effects elicited by 12, in the presence and absence of the allosteric activator ketanserin, were atypical and must be attributed to a mechanism, unknown up to now. In radioligand displacement experiments binding data for a set of nine compounds were determined at 5-HT1-like, 5-HT2 and 5-HT3 receptors, indicating subtype selectivity for some analogues. The binding affinity of 8 at 5-HT3 receptors which was comparable with the affinity of the selective 5-HT3 agonist 2-methyl-5-HT, could not be demonstrated on the longitudinal muscle strip of the guinea-pig ileum, partially due to the M3 antimuscarinic activity of 8. Functional studies on the rat oesophageal tunica muscularis mucosae did not reveal 5-HT4 agonist properties for two analogues of 5-methoxytryptamine (8, 16).