title: Structure activity relationships of a series of buspirone analogs at alpha-1 adrenoceptors: further evidence that rat aorta alpha-1 adrenoceptors are of the alpha-1D-subtype.
abstract: The activity of a series of busprione analogs at recombinant and rat thoracic aorta alpha-1 adrenoceptors was investigated. Compound affinity for recombinant alpha-1A, alpha-1B and alpha-1D adrenoceptors from human and animal sources was determined by radioligand binding assays using membranes prepared from rat-1 fibroblasts expressing recombinant receptors with ( +/- )-[125l]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone as the radioligand. Compound affinity and functional activity at rat aortic alpha-1 adrenoceptors were determined using endothelium denuded rings contracted with phenylephrine. BMY 7378 ¿8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ehtyl)-8-azaspiro [4,5]decane-7,9-dione dihydrochloride¿ and MDL 73005EF ¿8-[2-(1,4-benzodioxan-2-ylmethylamino) ethyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride¿ were found to have significant selectivity for the alpha-1D-subtype and were high affinity antagonists of the alpha-1 adrenoceptors in the rat aorta. Leverage plot analysis of affinities of the buspirone analogs and a series of structurally diverse alpha-1 antagonists for recombinant alpha-1 adrenoceptors and rat aorta alpha-1 adrenoceptors demonstrate that the alpha-1 adrenoceptors in the rat aorta are predominantly of the alpha-1D subtype.
authors.affiliation: Department of Receptor Biochemistry, Glaxo Wellcome Research and Development, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Saussy
authors.forename: A S
authors.initials: AS
authors.lastname: Goetz
authors.forename: K L
authors.initials: KL
authors.lastname: Queen
authors.forename: H K
authors.initials: HK
authors.lastname: King
authors.forename: M W
authors.initials: MW
authors.lastname: Lutz
authors.forename: T J
authors.initials: TJ
authors.lastname: Rimele
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002065:Buspirone / Q000494:pharmacology*; D002417:Cattle; D006224:Cricetinae; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D018340:Receptors, Adrenergic, alpha-1; D002065:Buspirone