[The synthesis and biological activity of substituted tetrahydroisoquinoline compounds].
Tetrandrine possesses calcium antagonistic and hypotensive effects. It was cleaved into two compounds O-methylcoclaurine (I) and N-methylarmepavine (II) by Na/NH3. Pharmacological test indicated that I and II showed weaker calcium antagonistic activity but having alpha-adrenoceptor antagonistic effect. With I and II as lead compounds as well as integration of some structural feature of calcium antagonists and SAR of antiarrhythmic drugs, two kinds of substituted tetrahydroisoquinoline derivatives III, IV were designed and synthesized in order to search for novel cardiovascular drugs. Tetrahydroisoquinoline compounds were first synthesized by the Bischler-Napiraski cyclization with substituted phenethylamine and aromatic acetic acid or substituted cinnamic acid as starting materials. N-alkylsubstituted tetrahydroisoquinoline compounds were prepared by the reaction of 4 with alkyl halide to produce 5, then reduction of 5 by KBH4 to give III13-25. The synthesis of N-alkylaminoethyl substituted tetrahydroisoquinoline compounds involved the reaction of 6 with chloroacetyl chloride to obtain IV1-3, the reaction of IV1-3 with secondary amine to produce 9, and then reduction of 9 with LiA1H4 to give IV16-19. Preliminary tests showed that most of these compounds exhibited varied degree of alpha-adrenoceptor antagonistic effect, and some of them possess calcium antagonistic activity. In anesthetic normal rats III15, 19 showed certain degree of hypotensive effect. IV10, 11 exhibited significant protective effect on experimental arrhythmic animals. The results of quantum chemical calculation of some compounds demonstrate that the compounds might act with alpha 1-adrenoceptor by forming charge-transfer complex.
Huang
W L
WL
Division of Medicinal Chemistry, China Pharmaceutical University, Nanjing.
Song
X Q
XQ
Peng
S X
SX
Huang
Z Y
ZY
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D007546:Isoquinolines / Q000138:chemical synthesis*; D051379:Mice; D051381:Rats; D044005:Tetrahydroisoquinolines
D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline