Pyrrolidino-tetrahydroisoquinolines as potent dual H3 antagonist and serotonin transporter inhibitors.
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.
Keith
John M
JM
Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA. jkeith@prdus.jnj.com
Gomez
Leslie A
LA
Wolin
Ronald L
RL
Barbier
Ann J
AJ
Wilson
Sandy J
SJ
Boggs
Jamin D
JD
Mazur
Curt
C
Fraser
Ian C
IC
Lord
Brian
B
Aluisio
Leah
L
Lovenberg
Timothy W
TW
Carruthers
Nicholas I
NI
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003863:Depression / Q000188:drug therapy; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D012701:Serotonin / Q000737:chemistry*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*
D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D044005:Tetrahydroisoquinolines