Differentiation between partial agonists and neutral 5-HT1B antagonists by chemical modulation of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy-N-[4-(pyridin-4-yl)phenyl]benzamide (GR-55562)

The synthesis and binding affinity at cloned h5-HT1B, h5-HT1D, and h5-HT1A receptors of 3-[3-(NN-dimethylamino)propyl]-4-hydroxy-N-[4- (2, GR-55562) and four 0-methylated analogs are described. The functional activity of these compounds was determined at the h5-HT1B receptor using a [S-35]GTP gamma S binding assay. The four analogs have been prepared in order to evaluate the influence of the alkylamino side chain conformation on binding and intrinsic activity. Whereas 2 and its derivatives display a similar binding affinity profile, major differences arise from analysis of the intrinsic activity data at h5-HT1B receptors. The 0-methylated analog of 2, 3-[3-(N,N-dimethylamino)propyl]-4-methoxy-N-[4-(pyridin-4-yl)phenyl]benzamide (3a), and the (1Z)-3-(N,N-dimethylamino)prop-1-enyl derivative (3c) act as neutral and potent antagonists (in a similar way to 2), while the 3-(N,N-dimethylamino)-prop-1-ynyl(3b) and(1E)-3-(N,N-dimethylamino)prop-1-enyl(3d) analogs display nonnegligible agonist activity. Molecular modeling studies show that, when the common triaryl portions of the molecules are overlapped, the partial agonists and the neutral antagonists differ by a near-orthogonal orientation of the NH- projection to the hydrogen-bend receptor site.