Inotropic and chronotropic effects of N6‐substituted derivatives of cyclic AMP as assessed in guinea‐pig isolated right atria and papillary muscle

1 The inotropic and chronotropic actions of N6‐substituted adenosine 3″:5″‐cyclic monophosphate (cyclic AMP) derivatives (N6‐R cyclic AMPs) were studied in guinea‐pig isolated right atrial preparations and in the papillary muscle preparations from guinea‐pig right ventricle. 2 All the N6‐R cyclic AMPs except N6‐C14H29 produced positive inotropic effects in papillary muscle. The C5H11, C6H13, C7H15, C8H17 and C9H19 compounds were the most potent as inotropic agents, the potency being lower with compounds having longer or shorter N6‐side chains than these. 3 In right atria N6‐C2H5‐C7H15 cyclic AMPs produced negative chronotropic effects. However, after treatment of the preparations with 8‐phenyltheophylline the negative chronotropic effects were either much attenuated or abolished, indicating the involvement of adenosine receptors. 4 All the N6‐R cyclic AMPs except N6‐C14H29 were more potent activators of bovine myocardial protein kinase than cyclic AMP. The partition coefficients between octanol and an aqueous phase of N6‐R cyclic AMPs became greater as the numbers of carbon atoms increased, and there appeared to be a relationship between partition coefficient and inotropic potency. It was concluded that membrane penetrativeness rather than potency as activators of protein kinase determined the potencies of N6‐R cyclic AMPs as positive inotropic agents. 5 Derivatives such as N6‐C7H15 cyclic AMP, which have positive inotropic activity without any marked negative chronotropic effect, may be useful as cardiotonic agents in heart failure.

[1]  Kenneth A. Jacobson,et al.  Analogues of Adenosine, Theophylline, and Caffeine: Selective Interactions with A1 and A2 Adenosine Receptors , 1987 .

[2]  T. Kawada,et al.  In Vivo and In Vitro Assessment of the Cardiovascular Effects of 8-(Benzylthio)-N6-n-Butyl–Cyclic AMP , 1985, Journal of cardiovascular pharmacology.

[3]  L. Opie.  Role of cyclic nucleotides in heart metabolism. , 1982, Cardiovascular research.

[4]  G. Burnstock,et al.  8-phenyltheophylline: a potent P1-purinoceptor antagonist. , 1981, European journal of pharmacology.

[5]  S H Snyder,et al.  Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. , 1981, Life sciences.

[6]  R. Graeff,et al.  4 – Cyclic Nucleotides and Cardiac Function , 1981 .

[7]  S. Imai,et al.  Inotropic and chronotropic actions of 2-substituted and 8-substituted derivatives of adenosine 3',5'-cyclic monophosphate. , 1980, Chemical & pharmaceutical bulletin.

[8]  R. K. Robins,et al.  Synthesis and enzymatic and inotropic activity of some new 8-substituted and 6,8-disubstituted derivatives of adenosine cyclic 3',5'-monophosphate. , 1980, Journal of medicinal chemistry.

[9]  D. Severson,et al.  Cyclic nucleotides and cardiac function. , 1979, Circulation research.

[10]  Margarete Müller,et al.  Adenosine inhibits the accumulation of cyclic AMP in cultured brain cells , 1978, Nature.

[11]  C. Londos,et al.  Two distinct adenosine-sensitive sites on adenylate cyclase. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Tsien.  Cyclic AMP and contractile activity in heart. , 1977, Advances in cyclic nucleotide research.

[13]  Laffan Rj,et al.  Stimulation of myocardial contractility by a new cyclic nucleotide analog, 8-(benzylthio)-N6-n-butyladenosine cyclic 3',5'-phosphate (SQ 80122). , 1976 .

[14]  D. B. Evans,et al.  Stimulation of myocardial contractility by a new cyclic nucleotide analog, 8-(benzylthio)-N6-n-butyladenosine cyclic 3',5'-phosphate (SQ 80122). , 1976, Journal of cyclic nucleotide research.

[15]  S. Imai,et al.  Positive inotropic and chronotropic effects of 8-substituted derivatives of 3',5'-cyclic AMP. , 1975, Japanese Journal of Pharmacology.

[16]  S. Imai,et al.  Effects of cyclic AMP and dibutyryl cyclic AMP on the heart and coronary circulation. , 1974, Japanese journal of pharmacology.

[17]  R. K. Robins,et al.  The chemistry and biological properties of nucleotides related to nucleoside 3',5'-cyclic phosphates. , 1973, Advances in cyclic nucleotide research.

[18]  S. Epstein,et al.  Positive Inotropic Effects of Dibutyryl Cyclic Adenosine 3′,5′‐Monophosphate , 1970, Circulation research.

[19]  P. Greengard,et al.  Cyclic nucleotide-dependent protein kinases. 3. Purification and properties of adenosine 3',5'-monophosphate-dependent protein kinase from bovine brain. , 1969, The Journal of biological chemistry.

[20]  T. N. James,et al.  The chronotropic action of ATP and related compounds studied by direct perfusion of the sinus node. , 1965, The Journal of pharmacology and experimental therapeutics.