title: Hybrid approach for the design of highly affine and selective dopamine D(3) receptor ligands using privileged scaffolds of biogenic amine GPCR ligands.
abstract: A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological screening was carried out at dopamine D(2) and D(3) receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D(3)receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD(3)K(i)=0.3 nM; hD(2)K(i)=703 nM), leading to a selectivity ratio of 2343.
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
authors.forename: Britta C
authors.initials: BC
authors.lastname: Sasse
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Mach
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppaenen
authors.forename: Thierry
authors.initials: T
authors.lastname: Calmels
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D017332:Cetirizine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007665:Ketotifen / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D017336:Loratadine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008803:Mianserin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship