title: Inhibition of muscarinic receptor binding and acetylcholine-induced contraction of guinea pig ileum by analogues of 5'-(isobutylthio)adenosine.
abstract: (Isobutylthio)adenosine (SIBA, 1) and its derivatives have been shown to produce a variety of biological effects on the basis of the hypothesis that such agents act directly as inhibitors of transmethylation reactions, as inhibitors of S-adenosylhomocysteine hydrolase, or as inhibitors of polyamine biosynthesis. We report here the ability of selected analogues of SIBA to inhibit the binding of the muscarinic antagonist quinuclidinyl benzilate (QNB) to cultured N4TG1 neuroblastoma cells and to antagonize the acetylcholine-induced contraction of guinea pig ileum. The most potent inhibitors were 5'-deoxy-5'-(isobutylthio)-1-deazaadenosine (1-deaza-SIBA, 5) and 5'-deoxy-5'-(isobutylthio)-3-deazaadenosine (3-deaza SIBA, 3), while the parent nucleoside SIBA and the carbocyclic derivative 5'-(isobutylthio)-3-deazaaristeromycin were less active. The same agents had no effect on the nicotinic receptors of NG108-15 neuroblastoma X glioma hybrid cells. The acyclic derivative 9-[[2-(isobutylthio)ethoxy]methyl]adenine, 3-deazaadenosine, 5'-(isobutylthio)tubercidin, and 5'-(isobutylamino)adenosine were inactive at the 1-mM level. These results suggest that SIBA and 3-deaza-SIBA may have profound effect on membrane-mediated phenomenon, including inhibition of muscarinic receptor binding.
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013872:Thionucleosides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D003839:Deoxyadenosines; D011976:Receptors, Muscarinic; D013872:Thionucleosides; C013919:5'-deoxy-5'-S-isobutylthioadenosine; D011813:Quinuclidinyl Benzilate; D000109:Acetylcholine