Selective alpha-1a adrenergic receptor antagonists. Effects of pharmacophore regio- and stereochemistry on potency and selectivity.

The anti-anxiety agent ipsapirone has been shown to have modest affinity for alpha-1 receptors. We disclose the discovery of potent alpha-1a receptor subtype selective antagonists based on the ipsapirone structure 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 structural motif are discussed. The synthesis of key analogs, their SAR, as well as results of selected in vitro and in vivo studies are described.