Synthesis, binding affinity and intrinsic activity of new anilide derivatives of serotonin at human 5-HT1D receptors

Summary The design and synthesis of a new series of anilide derivatives of serotonin is described. Binding affinity and intrinsic activity were evaluated at cloned human 5-HT IDα , 5-HT IDβ and 5-HT IA receptors. Modification of the terminal substituent on the aromatic moiety (R 1 ) was investigated and optimal affinity, activity and selectivity for 5-HT 1D versus 5-HT IA receptors were obtained for the sulfonamide derivatives 9 and 10 . Functional activity was also assessed in the New Zealand white rabbit saphenous vein contraction model, in which most of the compounds behaved as full agonists. Further structural modifications are also described, eg, replacement of the oxygen for carbon atom at the 5-position of the tryptamine moiety or terminal N -dimethylation.