Interaction of ebeinone, an alkaloid from Fritillaria imperialis, at two muscarinic acetylcholine receptor subtypes.
The ability of the alkaloid, ebeinone, isolated from Fritillaria imperialis, to act at muscarinic M2 and M3 acetylcholine receptors was investigated. In functional studies with guinea-pig left atrium, ebeinone was found to be ca. 10-fold more active as an antagonist of responses to carbachol (CCh) than in either guinea-pig ileum or trachea. Estimates of dissociation constants (KB values) in the three tissues were 77.3, 931.1 and 547.0 nM, respectively. Inhibition binding studies in rat atria with the non-selective antagonist [3H]N-methylscopolamine ([3H]NMS) showed ebeinone to have a KI value of 80.9 nM. Comparison of ebeinone with pancuronium, another steroid-like compound with a similar KB value at the muscarinic M2 receptor, found both compounds able to retard the dissociation rate of [3H]NMS in atria, indicating an allosteric mode of interaction at the M2 receptor. It is concluded that ebeinone exhibited a higher affinity for muscarinic M2 receptors than for M3 receptors in the guinea-pig and that it interacted allosterically at rat atrial M2 receptors.
Gilani
A H
AH
Department of Physiology and Pharmacology, Aga Khan University Medical College, Karachi, Pakistan.
Shaheen
F
F
Christopoulos
A
A
Mitchelson
F
F
D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D000495:Allosteric Site; D000818:Animals; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D010944:Plants / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D014132:Trachea / Q000378:metabolism
D000470:Alkaloids; D011976:Receptors, Muscarinic; C104693:ebeinone