Indanyl piperazines as melatonergic MT2 selective agents.
Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT(2) receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT(2) agonist, which produces advances in circadian phase in rats at doses of 1-56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.
Mattson
Ronald J
RJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA. mattsonr@bms.com
Catt
John D
JD
Keavy
Daniel
D
Sloan
Charles P
CP
Epperson
James
J
Gao
Qi
Q
Hodges
Donald B
DB
Iben
Lawrence
L
Mahle
Cathy D
CD
Ryan
Elaine
E
Yocca
Frank D
FD
D016475:3T3 Cells; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D044094:Receptors, Melatonin
D007202:Indicators and Reagents; D010879:Piperazines; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D000262:Adenylyl Cyclases