Abstract:
:Semiempirical quantum mechanical and molecular mechanics calculations were carried out to identify and characterize the steric and electronic properties that modulate ligand recognition and activation of the cerebellar GABAA/benzodiazepine (BDZ) receptor. For this hypothesis development, thirteen compounds belonging to structurally diverse chemical families were selected for study. Among the compounds selected were nine that bind and four that do not bind with appreciable affinity to this receptor and some that are known agonists, antagonists and inverse agonists, as measured by their modulation of GABA (gamma-aminobutyric acid) enhanced chloride ion flux in cerebellum. The stereoelectronic requirements for recognition deduced from commonalities among the ligands are the presence of at least two of three hydrogen bonding centers, and a lipophilic aromatic ring, in a specific spatial relationship. The results suggest that the selectivity for the cerebellar or Type I subtype, demonstrated by some of these ligands, could be failure to meet the requirements for binding at other receptors because of the absence of one of the proton accepting centers or the larger surface area and volume of these ligands. The requirement for activation, deduced from comparisons of agonist, antagonist, and inverse agonist properties is the presence of an electron accepting aromatic ring in a specific geometric arrangement with respect to the components of recognition. The validity of the '3D-Pharmacophore' developed was probed by using it for predictions of the behavior of 11 additional compounds not used for its development.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Schove LT,Perez JJ,Loew GHdoi
10.1016/s0968-0896(00)82053-2subject
Has Abstractpub_date
1994-10-01 00:00:00pages
1029-49issue
10eissn
0968-0896issn
1464-3391pii
S0968-0896(00)82053-2journal_volume
2pub_type
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journal_title:Bioorganic & medicinal chemistry
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