Inhibitory effects of adenine nucleotide analogs on the isolated guinea-pig taenia coli.
The inhibitory actions of adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine and 16 adenine nucleotide and nucleoside analogs on the isolated guinea-pig taenia coli preparation were compared with those of adenosine triphosphate (ATP). Responses were quantitated as magnitude of maximal relaxation, time taken to reach maximal relaxation and activity relative to that of ATP. Inhibitory responses induced by the 5'-di- and triphosphates of 2-chloroadenosine and 2-methylthioadenosine resembled those elicited by ADP and ATP, but the 2-substituted analogs were markedly more potent. AMP and adenosine were less active than ATP; their activities were enhanced by 2-chloro substitution but not by 2-methylthio substitution. 2-Methylthio-AMP and 2-methylthioadenosine were the only analogs which did not elicit maximal relaxation of the taenia coli. 6'-Deoxyhomoadenosine 6'-phosphonic acid was inactive. Adenine nucleotide analogs in which the polyphosphate moiety was modified had steeper log dose-response curves than ATP and induced greater maximal responses than ATP. Analogs in which the polyphosphate alpha, beta-anhydride oxygen was replaced by methylene took up to 5 times longer than ATP to cause maximal relaxation. Other analogs with modified or unmodified polyphosphate side chains caused rapid relaxation of the taenia coli. There was no apparent correlation between relative activity and time to reach maximal response. The findings obtained indicate that di- or triphosphate groupings are of prime importance in binding adenine nucleotides to the putative smooth muscle receptor which mediates their inhibitory responses, and that hydrolysis of the terminal phosphates of adenosine 5'-polyphosphates is not a requirement for inhibitory activity. Reasons for the distinctive inhibitory actions of the phosphate-modified adenine nucleotide analogs are considered.
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors
D000227:Adenine Nucleotides; D000241:Adenosine