BINDING OF O-ALKYL DERIVATIVES OF SEROTONIN AT HUMAN 5-HT1D-BETA RECEPTORS

In humans, 5-HT1D serotonin receptors represent terminal autoreceptors , and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatrip tan; however, this agent reportedly displays little selectivity for 5- HT1D versus 5-HT1A receptors. To identify novel serotonergic agents wi th enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take adv antage of possible differences in the regions of bulk tolerance associ ated with the 5-position of the 5-HT binding sites for these two popul ations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1D be ta receptors (K-i < 5 nM) but demonstrate less than 50-fold selectivit y relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups long er than nine carbon atoms lead to compounds with reduced affinity at 5 -HT1D beta receptors. 5-(Nonyloxy)tryptamine (10) represents a compoun d with optimal 5-HT1D beta affinity (K-i = 1 nM) and selectivity (>300 -fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tr yptamine (15), results in an agent with somewhat lower affinity (5-HT1 D beta K-i = 2.3 nM) hut with greater (i.e., 400-fold) 5-HT1D versus H T1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a car bonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or 8-carboline (i.e., 37), result in red uced affinity and/or selectivity. None of the compounds examined displ ayed significant selectivity for 5-HT1D beta versus 5-HT1D beta sites; nevertheless, compounds 10 (recently shown to behave as a 5-HT1D agon ist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents r eported to date.