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SCOPUS 학술저널

Pharmacological Characterization of Synthetic Tetrahydroisoquinoline Alkaloids, YS 51 and YS 55, on the Cardiovascular System

Pharmacological Characterization of Synthetic Tetrahydroisoquinoline Alkaloids, YS 51 and YS 55, on the Cardiovascular System

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<P> Tetrahydroisoquinoline (THI) alkaloids can be considered as cyclized derivatives of simple phenylethylamines, and many of them, especially with 6,7-disubstitution, demonstrate relatively high affinity for catecholamines. Two -OH groups at 6 and 7 positions are supposed to be essential to exert &#12546;-receptor activities. However, it is not clear whether -OH at 6,7 substitution of THIs also shows &#12545;-adrenoceptor activities. In the present study, we investigated whether -OH or -OCH<SUB>3</SUB> substitutions of 6,7 position of THIs differently affect the &#12545;<SUB>1</SUB>-adrenoceptor affinity. We synthesized two 1-naphthylmethyl THI alkaloids, 1-&#12546;-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline HBr (YS 51) and 1-&#12546;-naphthylmethyl-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline HCl (YS 55), and their pharmacological actions on &#12545;<SUB>1</SUB>-adrenoceptor were compared. YS 51 and YS 55, concentration-dependently relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 &#12557;M) in which pEC<SUB>50</SUB> were 5.89&#8290;0.21 and 5.93&#8290;0.19, respectively. Propranolol (30 nM) did not affect the relaxation-response curves to YS 51 and YS 55. Concentration-response curves to PE were shifted to right by the pretreatment with YS 51 or YS 55. The pA<SUB>2</SUB> values of YS 51 and YS 55 showed 6.05&#8290;0.24 and 5.88&#8290;0.16, respectively. Both probes relaxed KCl (65.4 mM)-contracted aorta and inhibited CaCl<SUB>2</SUB>-induced contraction of PE-stimulated endothelium- denuded rat thoracic aorta in Ca<SUP>2&#8290;</SUP>-free solutions. In isolated guinea pig papillary muscle, 1 and 10 &#12557;M YS 51 increased contractile force about 4- and 8- fold over the control, respectively, along with the concentration-dependent increment of cytosolic Ca<SUP>2&#8290;</SUP> ions. While, 10 &#12557;M YS 55 reduced the contractile force about 50 % over the control and lowered the cytosolic Ca<SUP>2&#8290;</SUP> level, in rat brain homogenates, YS 51 and YS 55 displaced [<SUP>3</SUP>H]prazosin binding competitively with K<I>i</I> 0.15 and 0.12 &#12557;M, respectively. However, both probes were ineffective on [<SUP>3</SUP>H]nitrendipine binding. Therefore, it is concluded that two synthetic naphthylmethyl-THI alkaloids have considerable affinity to &#12545;<SUB>1</SUB>-adrenenoceptors in rat aorta and brain.

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