RESUMO
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 beta-receptor activities. However, it is not clear whether -OH at 6,7 substitution of THIs also shows alpha-adrenoceptor activities. In the present study, we investigated whether -OH or -OCH3 substitutions of 6,7 position of THIs differently affect the alpha1-adrenoceptor affinity. We synthesized two 1-naphthylmethyl THI alkaloids, 1-beta-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline HBr (YS 51) and 1-beta-naphthylmethyl-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline HCl (YS 55), and their pharmacological actions on alpha1-adrenoceptor were compared. YS 51 and YS 55, concentration-dependently relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 micrometer) in which pEC50 were 5.89+0.21 and 5.93+ 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 pA2 values of YS 51 and YS 55 showed 6.05 + 0.24 and 5.88 + 0.16, respectively. Both probes relaxed KCl (65.4 mM)-contacted aorta and inhibited CaCl2-induced contraction of PE-stimulated endothelium-denuded rat thoracic aorta in Ca2+-free solutions. In isolated guinea pig papillary muscle, 1 and 10 micrometer YS 51 increased contractile force about 4- and 8- fold over the control, respectively, along with the concentration-dependent increment of cytosolic Ca2+ ions. While, 10 micrometer YS 55 reduced the contractile force about 50 % over the control and lowered the cytosolic Ca2+ level, in rat brain homogenates, YS 51 and YS 55 displaced (3H)prazosin binding competitively with Ki 0.15 and 0.12 micrometer, respectively. However, both probes were ineffective on (3H)nitrendipine binding. Therefore, it is concluded that two synthetic naphthylmethyl-THI alkaloids have considerable affinity to alpha1-adrenenoceptors in rat aorta and brain.