Synthesis and substance P antagonist activity of naphthimidazolium derivatives.
The synthesis of unsymmetrical naphth[2,3-d]imidazolium and bridged naphth[2,3-d]imidazolium derivatives and their substance P (SP) antagonist activity are described. All compounds were evaluated for their ability to displace SP from neurokinin-1 (NK-1) receptor sites using standard receptor binding methodology (rat forebrain membrane). 1,3-Diethyl-2-[3-(1,3-dihydro-1,3,3-timethyl-2H-indol-2-ylidene) -1-propenyl]-1H-naphth[2,3-d]imidazolium chloride (7a), a representative compound in this series, was further evaluated for SP antagonist activity in a guinea pig ileum contractility assay. In vivo SP antagonist activity of 7a was demonstrated using SP-induced salivation and paw edema models performed in rats.
Lawrence
K B
KB
Life Sciences Research Laboratories, Eastman Kodak Company, Rochester, New York 14650-2158.
Venepalli
B R
BR
Appell
K C
KC
Goswami
R
R
Logan
M E
ME
Tomczuk
B E
BE
Yanni
J M
JM
D000818:Animals; D001667:Binding, Competitive; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007093:Imidazoles; D007211:Indoles; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; C074027:1,3-diethyl-2-(3-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-1-propenyl)-1H-naphth(2,3-d)imidazolium; D013373:Substance P