Inhibition of brain [(3)H]cimetidine binding by improgan-like antinociceptive drugs.
[(3)H]cimetidine, a radiolabeled histamine H(2) receptor antagonist, binds with high affinity to an unknown hemoprotein in the brain which is not the histamine H(2) receptor. Improgan, a close chemical congener of cimetidine, is a highly effective pain-relieving drug following CNS administration, yet its mechanism of action remains unknown. To test the hypothesis that the [(3)H]cimetidine-binding site is the improgan antinociceptive target, improgan, cimetidine, and 8 other chemical congeners were studied as potential inhibitors of [(3)H]cimetidine binding in membrane fractions from the rat brain. All compounds produced a concentration-dependent inhibition of [(3)H]cimetidine binding over a 500-fold range of potencies (K(i) values were 14.5 to >8000nM). However, antinociceptive potencies in rats did not significantly correlate with [(3)H]cimetidine-binding affinities (r=0.018, p=0.97, n=10). These results suggest that the [(3)H]cimetidine-binding site is not the analgesic target for improgan-like drugs.
Stadel
Rebecca
R
Center for Neuropharmacology and Neuroscience, Albany Medical College, NY 12208, USA.
Carpenter
Amanda B
AB
Nalwalk
Julia W
JW
de Esch
Iwan J P
IJ
Janssen
Elwin
E
Hough
Lindsay B
LB
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D010146:Pain / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D006635:Histamine H2 Antagonists; C099531:SKF 92374; D002927:Cimetidine; D006632:Histamine