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Tetrahydroprotoberberine analogs antagonize α 1 ‐adrenoceptors and inhibit mobilization of intracellular calcium
Author(s) -
Han Chide,
Lu Zhizheng,
Wei Xuan,
Jin Guozhang
Publication year - 1996
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199610)39:2<191::aid-ddr13>3.0.co;2-f
Subject(s) - phenylephrine , schild regression , chemistry , intracellular , bradykinin , contraction (grammar) , calcium , radioligand , calcium in biology , endocrinology , pharmacology , medicine , biological activity , angiotensin ii , receptor , stereochemistry , biochemistry , agonist , biology , in vitro , organic chemistry , blood pressure
Effect of tetrahydroprotoberberine (THPB) analogues 1 ‐stepholidine ( 1 ‐SPD), 1 ‐tetrahydropalmatine ( 1 ‐HTP), tetrahydroberberine (THB), and tetrahydroproberberine‐18 (THPB‐18) on α 1 ‐adrenoceptors and cellular Ca 2+ 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 125 I‐BE 2254 binding to α 1 ‐adrenoceptors with pK i values (‐log K i ) 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 pA 2 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 CaCl 2 ‐induced contraction in calcium free Krebs solution containing 100 mM KCl. However, both of them noncompetitively inhibited vasocontraction induced by intracellular Ca 2+ mobilizers phenylephrine, 5‐HT, angiotensin II, or bradykinin. These results suggest that THPB analogs can non‐subtype selectively antagonize α 1 ‐adrenoceptors and inhibit intracellular Ca 2+ mobilization. Drug Dev. Res. 39:191–196. © 1997 Wiley‐Liss, Inc.