Journal of Medicinal Chemistry p. 39 - 44 (1990)
Update date:2022-08-23
Topics:
Gao, Yigong
Ram, Vishnu J.
Campbell, Alexander
Kula, Nora S.
Baldessarini, Ross J.
Neumeyer, Johm L.
A series of N-substituted analogues of (R)-(-)-naorapomorphine 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.Evaluation 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 lipohilic 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 <*> 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-pentafluoropropyl (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.
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