Dual serotonin transporter inhibitor/histamine H3 antagonists: development of rigidified H3 pharmacophores.
A series of tetrahydroisoquinolines acting as dual serotonin transporter inhibitor/histamine H(3) antagonists is described. The introduction of polar aromatic spacers as part of the histamine H(3) pharmacophore was explored. A convergent synthesis of the final products allowing late stage introduction of the aromatic side chain 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, San Diego, CA 92121, USA. jkeith@prdus.jnj.com
Barbier
Ann J
AJ
Wilson
Sandy J
SJ
Miller
Kirstin
K
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; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*
D006633:Histamine Antagonists; D007202:Indicators and Reagents; D018100:Receptors, Histamine H3; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D044005:Tetrahydroisoquinolines; D006916:5-Hydroxytryptophan