Enhancement of adenosine A1 receptor functions by benzoylthiophenes in guinea pig tissues in vitro

Previous reports on a series of benzoylthiophenes, including PD 81,723 {2-amino-4,5-dimethyl-3-(3-trifluoromethyl-benzoyl)thiophene}, have shown specific enhancement of agonist binding at the adenosine A₁ receptor. We have studied the effects of two substituted benzoylthiophenes, PD 78,416 {thieno[2,3-c]pyridine-6(5H)-carboxylic acid, 2-amino-3-benzoyl-4,7-dihydro-ethyl ester} and RS-74513-000 {2-amino-4-ethyl-5-methyl-3-(3-trifluoro-methyl-benzoyl) thiophene} on response elicited by adenosine A₁ receptors in isolated guinea pig left atrium and ileum.In the electrically paced left atrium, PD 78,416 antagonized negative inotropic effect elicited by the agonist CPA {N⁶-cyclopentyladenosine} with a pK_B value of 6.2 ± 0.2 (n = 4) . At a low concentration which had no antagonistic effect (0.1 M), PD 78,416 enhanced the effect of CPA. The concentration-response curve to CPA was shifted leftward by 5.1 fold (95% confidence limits 2.4–11.2). In field stimulated isolated ileum, PD 78,416 (0.1, 0.3, 1 M) did not enhance or antagonize effects of CPA. At concentrations above 1 M, PD 78,416 decreased electrically induced contraction. This effect was not sensitive to adenosine deaminase and was not antagonized by the A₁ antagonist CPX {8-cyclopentyl-1,3-dipropyl-xanthine} (1 M).Unlike PD 78,416, RS-74513-000 (0.01, 0.1, 1, 3, 10 M) did not antagonize or enhance effects of CPA in the left atrium. However, effects of CPA in ileum were enhanced by RS-74513-000 (1 and 3 M). Maximum enhancement was observed at 3 M; the concentration-response curve to CPA was shifted leftward by 3.2 fold (95% confidence limits 2.4–4.2). Higher concentrations of RS-74513-000 (10 and 30 M) decreased electrically induced contraction, this effect was not reversed by CPX. These findings confirmed that functional effects of A₁ adenosine receptor may be enhanced by substituted benzoylthiophenes in vitro. The differential effect of PD 78,416 and RS-74513-000 on cardiac and ileal A₁ receptors suggests that it may be possible to design selective enhancers for cardiac and neural functions.