The current study describes the synthesis and biol. evaluation of a novel series of 2-amino-3-naphthoylthiophenes, with variable modifications at the 4- and 5-position of the thiophene as well as the naphthoyl ring. Allosteric enhancer activity was measured in several ways: (1) evaluating the effect on forskolin-stimulated cAMP accumulation in the presence of an A1-adenosine agonist (CPA) in Chinese hamster ovary (CHO) cells expressing the cloned human A1-adenosine receptor (hA1AR); (2) ability of these compds. to displace the binding of [3H]DPCPX, [3H]ZM 241385, and [3H]MRE 3008F20 to the ligand binding site of CHO cells expressing the hA1, hA2A, and hA3 adenosine receptors, resp.; (3) effect on the binding of [3H]CCPA to membranes from CHO cells expressing hA1AR, to rat brain and human cortex membrane prepns. contg. native adenosine A1 receptors; (4) kinetics of the dissocn. of [3H]CCPA from CHO-hA1 membranes. The pharmacol. assays compared the various activities to that of the ref. compd. PD 81,723. Several compds. appeared to be better than PD 81,723 to enhance the effect of CPA (and thus reduce cAMP content) in the CHO:hA1 assay. The effect of these compds. at a concn. of 10 M was slightly greater than that of the same concn. of the PD 81,723 and substantially greater than that of PD 81,723 when responses to 1 M of each compd. were compared. Cycloalkylthiophenes tended to be more potent then their 4,5-di-Me analogs, and in the series of cycloalkylthiophenes, tetrahydrobenzo[b]thiophene derivs. appeared to be more potent than the dihydrocyclopentadien[b]thiophene counterparts. Some of the most potent compds. were tested at a concn. of 10 M for their affinity as competitors to the antagonist binding site of CHO cells expressing hA1, hA2A, and hA3 adenosine receptors. None inhibited binding at the hA2AAR, but most of them inhibited binding to the hA1AR to varying extents (0-19%) as well as to the hA3AR to a substantial degree (0-57%). A good correlation was found between the increments [3H]CCPA binding to A1 receptors expressed in different systems. Unlike the effect on agonist binding, the tested compds. did not increase the binding of the antagonist [3H]DPCPX on hCHO-A1 membranes. No clear-cut structure-activity relation can be obsd. based on data from the functional assay, but we have identified several compds. which appeared to be more potent than PD 81,723 and that may be selected for further development.
Synthesis and biological effects of novel 2-amino-3-naphthoylthiophenes as allosteric enhancers of the A(1) adenosine receptor
Baraldi P. G.;Romagnoli R.;Merighi S.;Borea P. A.
2003
Abstract
The current study describes the synthesis and biol. evaluation of a novel series of 2-amino-3-naphthoylthiophenes, with variable modifications at the 4- and 5-position of the thiophene as well as the naphthoyl ring. Allosteric enhancer activity was measured in several ways: (1) evaluating the effect on forskolin-stimulated cAMP accumulation in the presence of an A1-adenosine agonist (CPA) in Chinese hamster ovary (CHO) cells expressing the cloned human A1-adenosine receptor (hA1AR); (2) ability of these compds. to displace the binding of [3H]DPCPX, [3H]ZM 241385, and [3H]MRE 3008F20 to the ligand binding site of CHO cells expressing the hA1, hA2A, and hA3 adenosine receptors, resp.; (3) effect on the binding of [3H]CCPA to membranes from CHO cells expressing hA1AR, to rat brain and human cortex membrane prepns. contg. native adenosine A1 receptors; (4) kinetics of the dissocn. of [3H]CCPA from CHO-hA1 membranes. The pharmacol. assays compared the various activities to that of the ref. compd. PD 81,723. Several compds. appeared to be better than PD 81,723 to enhance the effect of CPA (and thus reduce cAMP content) in the CHO:hA1 assay. The effect of these compds. at a concn. of 10 M was slightly greater than that of the same concn. of the PD 81,723 and substantially greater than that of PD 81,723 when responses to 1 M of each compd. were compared. Cycloalkylthiophenes tended to be more potent then their 4,5-di-Me analogs, and in the series of cycloalkylthiophenes, tetrahydrobenzo[b]thiophene derivs. appeared to be more potent than the dihydrocyclopentadien[b]thiophene counterparts. Some of the most potent compds. were tested at a concn. of 10 M for their affinity as competitors to the antagonist binding site of CHO cells expressing hA1, hA2A, and hA3 adenosine receptors. None inhibited binding at the hA2AAR, but most of them inhibited binding to the hA1AR to varying extents (0-19%) as well as to the hA3AR to a substantial degree (0-57%). A good correlation was found between the increments [3H]CCPA binding to A1 receptors expressed in different systems. Unlike the effect on agonist binding, the tested compds. did not increase the binding of the antagonist [3H]DPCPX on hCHO-A1 membranes. No clear-cut structure-activity relation can be obsd. based on data from the functional assay, but we have identified several compds. which appeared to be more potent than PD 81,723 and that may be selected for further development.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
