- 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
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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.
- Gao, Yigong,Ram, Vishnu J.,Campbell, Alexander,Kula, Nora S.,Baldessarini, Ross J.,Neumeyer, Johm L.
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- 1-POLYHALOGENOALKYL-2-OXO-1,3-DIHYDRO-2H-1,4-BENZODIAZEPINES
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This invention relates to 2-oxo-1,3-dihydro-2H-1,4-dibenziodiazepines, and the 4-N-oxides thereof, having a polyfluoroalkyl radical attached at the 1-position thereof, to their use as muscle relaxants, as sedatives, an anticonvulsants, and as anti-anxiety agents and to the intermediates useful in the preparation thereof. The compounds may be prepared by N-polyfluoroalkylating the appropriately substituted 2-oxo-1,3-dihydro-2H-1,4-benzodiazepines. Alternate methods for the synthesis of the compounds of this invention are also described
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