Tetrahydroprotoberberine analogs antagonize ?1-adrenoceptors and inhibit mobilization of intracellular calcium

Abstract

Effect of tetrahydroprotoberberine (THPB) analogues 1-stepholidine (1-SPD), 1-tetrahydropalmatine (1-HTP), tetrahydroberberine (THB), and tetrahydroproberberine-18 (THPB-18) on α1-adrenoceptors and cellular Ca2+ dynamics were studied by radioligand binding assay and vascular contractile functional determination. In membrane preparations of rat cerebral cortex 1-SPD, 1-THP, THB, or THPB-18 inhibited 125I-BE 2254 binding to α1-adrenoceptors with pKi values (-log Ki) of 5.54 ± 0.36, 5.56 ± 0.47, 6.01 ± 0.60, and 5.75 ± 0.56, respectively. The Hill coefficients for the 4 analogs were not significantly different to unity. The computer analysis showed that the competitive curves for the 4 analogs were fit to a one binding site model. In isolated rat aortae 1-SPD, 1-THP, THB, or THPB-18 inhibited phenylephrine-induced contraction with pA2 values of 5.48 ± 0.58, 5.66 ± 0.54, 5.45 ± 0.76, and 5.64 ± 0.34, respectively; the slopes of the Schild plot were not significantly different from unity. 1-SPD (10 μM) and THB (10 μM) did not affect the CaCl2-induced contraction in calcium free Krebs solution containing 100 mM KCl. However, both of them noncompetitively inhibited vasocontraction induced by intracellular Ca2+ mobilizers phenylephrine, 5-HT, angiotensin II, or bradykinin. These results suggest that THPB analogs can non-subtype selectively antagonize α1-adrenoceptors and inhibit intracellular Ca2+ mobilization. Drug Dev. Res. 39:191–196. © 1997 Wiley-Liss, Inc.