11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.

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Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM

11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.

J Med Chem. 1996 Aug 30;39(18):3503-13.

PubMed ID

8784448 [ View in PubMed

]

Abstract

A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Apomorphine	Dopamine D2 receptor	Ki (nM)	41.9	N/A	N/A	Details