ABSTRACT
A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed.
Subject(s)
Histamine H1 Antagonists/pharmacology , Pyrrolidines/pharmacology , Receptors, Histamine H3/drug effects , Serotonin Plasma Membrane Transport Proteins/drug effects , Tetrahydroisoquinolines/pharmacology , Animals , Blood-Brain Barrier , Histamine H1 Antagonists/chemistry , Mice , Pyrrolidines/chemistry , Structure-Activity Relationship , Tetrahydroisoquinolines/chemistryABSTRACT
A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Receptors, Histamine H3/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/chemistry , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacology , Animals , Depression/drug therapy , Drug Design , Humans , Kinetics , Models, Chemical , Molecular Conformation , RatsABSTRACT
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.
Subject(s)
Receptors, Histamine H3/chemistry , Receptors, Histamine H3/drug effects , Serotonin Plasma Membrane Transport Proteins/drug effects , 5-Hydroxytryptophan/pharmacology , Animals , Behavior, Animal/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Ligands , Mice , Piperazines/chemical synthesis , Piperazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
