SYNTHESIS AND STRUCTURAL REQUIREMENTS OF N-SUBSTITUTED NORAPOMORPHINES FOR AFFINITY AND ACTIVITY AT DOPAMINE-D-1, D-2, AND AGONIST RECEPTOR-SITES IN RAT-BRAIN

被引:31
作者
GAO, YG
RAM, VJ
CAMPBELL, A
KULA, NS
BALDESSARINI, RJ
NEUMEYER, JL
机构
[1] NORTHEASTERN UNIV,COLL PHARM & ALLIED HLTH PROFESS,MED CHEM SECT,BOSTON,MA 02115
[2] HARVARD UNIV,SCH MED,DEPT PSYCHIAT,BOSTON,MA 02115
[3] HARVARD UNIV,SCH MED,NEUROSCI PROGRAM,BOSTON,MA 02115
[4] MCLEAN HOSP,MAILMAN RES CTR,BELMONT,MA 02178
关键词
D O I
10.1021/jm00163a007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of N-substituted analogues of (R)-(-)-norapomorphine were synthesized to study the optimal structural requirements of the N-alkyl side chain to interact with D-1 and D-2 dopaminergic receptors as well as dopamine (DA) agonist binding sites. Evaluations included testing the affinity of these compounds for DA receptor sites in rat striatal tissue and assessing stereotypy as a behavioral index of dopaminergic activity. The electronic, steric, and lipophilic properties of the N-alkyl side chain were found to be related to affinity, D-2 selectivity, and dopaminergic activity. All 11 compounds evaluated had relatively low affinity at D-1 sites. Optimum D-2 and agonist-site affinity as well as agonist activity were exhibited by N-cyclopropylmethyl (7) ≥ N-allyl (8) ≥ N-propyl (4) or N-ethyl (3) substituted compounds. Branching of the N-alkyl side chain as in N-isopropyl (5) and N-isobutyl (6) markedly reduced the D-2 affinity and activity, presumably due to steric effects. The N-trifluoroethyl (10) and N-penta-fluoropropyl (11) derivatives had low affinity for all their dopamine receptor sites and no agonistic activity; evidently, the highly electronegative F atoms decrease basicity of the N atom and therefore decrease the ability of the N atom to be cationic at physiological pH, a proposed requirement for high-affinity binding to DA receptors. © 1990, American Chemical Society. All rights reserved.
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页码:39 / 44
页数:6
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