Topography and conformational preferences of 6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6- ylamin e. A rationale for the dopaminergic inactivity.
In an attempt to rationalize the inability of phenolic benzocycloheptenylamines to activate dopamine (DA) D2 receptors, we have studied the conformational preferences and topography of 6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6-++ +ylamine (1). Preferred conformations of 1 have been defined by use of experimental (NMR spectroscopic studies) and theoretical (MMP2, AM1, and MNDO calculations) methods. Topographical characteristics were studied by use of molecular graphics. Results from the MMP2 calculations agree with those from the AM1 calculations and the NMR spectroscopic study--1 seems to preferentially adopt chair conformations with a pseudoequatorial C6 substituent. The MNDO calculations, however, produced results that deviate considerably from those of the other theoretical methods. Most likely, pharmacophore conformations of (S)-1 do not present volumes that are part of the DA D2 receptor essential volume. Therefore, it appears that the energy penalty paid by the pharmacophore conformations is responsible for the dopaminergic inactivity of (S)-1. The inactivity of (R)-1 may be due to high energies of pharmacophore conformations and/or to steric factors since these conformations produce large excess volumes that may be part of the DA D2 receptor essential volume. The model used in the present report--a flexible pharmacophore combined with a partial receptor-excluded volume--might be used in the design of new DA D2 receptor agonists.
Karlén
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A
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, University of Uppsala, Sweden.
Helander
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A
Kenne
L
L
Hacksell
U
U
D001567:Benzocycloheptenes / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003196:Computer Graphics; D003198:Computer Simulation; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D013329:Structure-Activity Relationship
D001567:Benzocycloheptenes; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; C059110:6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6-ylamine