SELECTIVE ALPHA-1A ADRENERGIC-RECEPTOR ANTAGONISTS - EFFECTS OF PHARMACOPHORE REGIO-CHEMISTRY AND STEREOCHEMISTRY ON POTENCY AND SELECTIVITY

The anti-anxiety agent ipsapirone has been shown to have modest affini ty for alpha-1 receptors. We disclose the discovery of potent alpha-1a receptor subtype selective antagonists based on the ipsapirone struct ure which possess selectivity versus the 5-HT receptors tested. These antagonists were obtained by tethering a saccharin ring to 4-phenyl-3- carboxyethyl piperidines. The design principles which led to this stru ctural motif are discussed. The synthesis of key analogs, their SAR, a s well as results of selected in vitro and in vivo studies are describ ed. (C) 1998 Elsevier Science Ltd. All rights reserved.