title: Molecular design of novel ligands for 5-HT1A receptors.
abstract: Serotonin (5-HT) is a potent bioactive substance known to function through a number of different receptor types and subtypes. In our attempt to develop new agents that would interact selectively at certain 5-HT receptors, especially the 5-HT1A subtype, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) served as a template for the design of novel agents sharing aspects of the pharmacophore of 8-OH-DPAT and 5-HT. 5-HT contains no center of asymmetry, and 8-OH-DPAT shows only very modest stereospecificity for 5-HT1A receptors. To develop agents having enhanced potency and selectivity for the 5-HT1A site, several ring systems offering enhanced conformational rigidity which approximate the oxygen to nitrogen interatomic distances of 8-OH-DPAT and (to a lesser extent) 5-HT were synthesized. Exemplary ring systems include the 8-alkoxy-hexahydroindeno[1,2-c]pyrrole, 5-alkoxy-hexahydro-1H-indeno-[2,1-c]pyridine, and 9-alkoxy-hexahydro-1H-benz[e]isoindole systems. These conformationally restricted molecules demonstrated moderate stereospecificity in their interaction with the 5-HT1A binding site, which was enhanced in compounds with larger nitrogen substituents. Appropriate choice of such derivatives led to highly potent compounds selective for 5-HT1A sites compared with their activity at other 5-HT and/or adrenergic receptors. The pharmacological profile of compounds which appear to act as agonists at 5-HT1A receptors in the central nervous system to lower blood pressure in animal models of hypertension is presented.
authors.affiliation: Cardiovascular Research Division, Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: A A
authors.initials: AA
authors.lastname: Hancock
authors.forename: M D
authors.initials: MD
authors.lastname: Meyer
authors.forename: J F
authors.initials: JF
authors.lastname: DeBernardis
mesh_terms: D000818:Animals; D001681:Biological Assay; D002319:Cardiovascular System / Q000503:physiopathology; D004285:Dogs; D015195:Drug Design; D066298:In Vitro Techniques; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011985:Receptors, Serotonin