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

<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.