title: Synthesis and serotonergic activity of variously substituted (3-amido)phenylpiperazine derivatives and benzothiophene-4-piperazine derivatives: novel antagonists for the vascular 5-HT1B receptor.
abstract: The synthesis and vascular 5-HT(1B) receptor activity of a novel series of substituted 3-amido phenylpiperazine and 4-(4-methyl-1-piperazinyl)-1-benzo[b]thiophene derivatives is described. Modifications to the amido linked sidechains of the 3-amidophenyl-piperazine derivatives and to the 2-sidechain of the 1-benzo[b]thiophene derivatives have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT(1B) receptor of pK(B) > 7.0. From the 3-amidophenyl-piperazine series, N-(4-(4-chlorophenyl)thiazol-2-yl-3-(4-methyl-1-piperazinyl)benzamide (30) and from the benzo[b]thiophene-4-piperazine series N-(2-ethylphenyl)-4-(4-methyl-1- piperazinyl)-1-benzo[b]thiophene-2-carboxamide (38) were identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT(1B) receptor mediated agonist activity in the rabbit femoral artery) and competitive vascular 5-HT(1B) receptor antagonist. The affinity of compounds from these two series of compounds for the vascular 5-HT(1B) receptor is discussed as well as a proposed mode of binding to the receptor pharmacophore.
authors.affiliation: Department of Medicinal Chemistry, The Victorian College of Pharmacy (Monash University), 381 Royal Parade, Parkville, Vic. 3052, Australia. gerard.moloney@vcp.monash.edu.au
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Moloney
authors.forename: Agatha
authors.initials: A
authors.lastname: Garavelas
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Martin
authors.forename: Miles
authors.initials: M
authors.lastname: Maxwell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Glen
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D012501:Saphenous Vein / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry
chemical_list: D000577:Amides; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D013876:Thiophenes; C088015:benzothiophene; C031503:phenylpiperazine