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-HT1D, h5-HT1D, and h5-HT1A receptors of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy- N-[4-(pyridin-4-yl)phenyl]benzamide (2, GR-55562) and four O-methylated analogs are described. The functional activity of these compounds was determined at the h5-HT1B receptor using a [35S]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 O-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-bond receptor site.