Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore.
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.
Keith
John M
JM
Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. jkeith@prdus.jnj.com
Gomez
Leslie A
LA
Letavic
Michael A
MA
Ly
Kiev S
KS
Jablonowski
Jill A
JA
Seierstad
Mark
M
Barbier
Ann J
AJ
Wilson
Sandy J
SJ
Boggs
Jamin D
JD
Fraser
Ian C
IC
Mazur
Curt
C
Lovenberg
Timothy W
TW
Carruthers
Nicholas I
NI
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000187:drug effects*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; D013329:Structure-Activity Relationship
D007546:Isoquinolines; D008024:Ligands; D010879:Piperazines; D018100:Receptors, Histamine H3; D050486:Serotonin Plasma Membrane Transport Proteins; D006916:5-Hydroxytryptophan