Aprophit: an irreversible antagonist for muscarinic receptors.
The development of selective irreversible ligands has proven to be an invaluable technique for the isolation, purification and characterization of many receptor proteins. An isothiocyanato-derivative of the muscarinic antagonist aprophen was synthesized and evaluated as a potential irreversible ligand for muscarinic receptors. This compound (aprophit) displaced [3H]N-methylscopolamine binding from rat cerebral cortex with a Ki of 3.1 x 10(-7) M. The inhibition was concentration-dependent and could not be reversed by extensive washing. Aprophit inhibited the acetylcholine-stimulated release of catecholamines from isolated, perfused guinea pig adrenal glands in a concentration-dependent manner. This inhibition was not reversed by perfusing the tissue with Locke's solution and was not due to a non-selective acylation by the isothiocyanate function. The data suggest that aprophit is selectively acylating muscarinic receptor proteins and thus may be useful in their further characterization.
Department of Applied Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
A H
AH
Newman
J
J
Covington
M
M
Oleshansky
B W
BW
Jackson
B A
BA
Weissman
H
H
Leader
P K
PK
Chiang
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D019832:N-Methylscopolamine; D010276:Parasympatholytics / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology*; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013861:Thiocyanates / Q000494:pharmacology*
D002395:Catecholamines; D010276:Parasympatholytics; D010666:Phenylpropionates; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D013861:Thiocyanates; C065764:aprophit; D010890:Pirenzepine; D001285:Atropine; C006615:aprofen; D019832:N-Methylscopolamine