SYNTHESIS, BINDING-AFFINITY AND INTRINSIC ACTIVITY OF NEW ANILIDE DERIVATIVES OF SEROTONIN AT HUMAN 5-HT1D RECEPTORS

The design and synthesis of a new series of anilide derivatives of ser otonin is described. Binding affinity and intrinsic activity were eval uated at cloned human 5-HT1D alpha, 5-HT1D beta and 5-HT1A receptors. Modification of the terminal substituent on the aromatic moiety (R(1)) was investigated and optimal affinity, activity and selectivity for 5 -HT1D versus 5-HT1A receptors were obtained for the sulfonamide deriva tives 9 and 10. Functional activity was also assessed in the New Zeala nd 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 t he 5-position of the tryptamine moiety or terminal N-dimethylation.