Dual serotonin transporter/histamine H3 ligands : Optimization of the H3 pharmacophore

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 3; pp. 702 - 706
• Main Authors: KEITH, John M, GOMEZ, Leslie A, MAZUR, Curt, LOVENBERG, Timothy W, CARRUTHERS, Nicholas I, LETAVIC, Michael A, LY, Kiev S, JABLONOWSKI, Jill A, SEIERSTAD, Mark, BARBIER, Ann J, WILSON, Sandy J, BOGGS, Jamin D, FRASER, Ian C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.02.2007
• Subjects: 5-Hydroxytryptophan - pharmacology; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Humans; Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; Ligands; Medical sciences; Mice; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - pharmacology; Rats; Receptors, Histamine H3 - chemistry; Receptors, Histamine H3 - drug effects; Serotonin Plasma Membrane Transport Proteins - drug effects; Structure-Activity Relationship; Ligand; Blood brain barrier; Modeling; Optimization; Structure activity relation; Membrane transport; Chemical synthesis; Carrier protein; Histamine H3; H3 histamine receptor; Isoquinoline derivatives; Regioselectivity; Serotonin; Rodentia; 5-HTP potentiation; In vitro; In vivo; Vertebrata; Mammalia; Serotonin transporter; Cyclization; Mouse; Animal; Neurotransmitter; Ring-closure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.10.089

A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.