- Studies in the search for α5 subtype selective agonists for GABA(A)/BzR sites
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In the search for α5 selective ligands, several series of diazepam analogs with individual and/or simultaneous modifications at positions-2, -5 and -7 were prepared and their in vitro affinities determined on recombinant receptors. These ligands were deliberately designed to test the effects of interaction at H1, H2, L2 and L3 of the pharmacophore/receptor model on ligand binding affinities and selectivities at different GABA(A)/BzR subtypes. In agreement with previous reports, none of these 1,4- benzodiazepines bound to the α4β3γ2 and α6β3γ2 receptor isoforms, two diazepam-insensitive(DI) GABA(A) receptor subtypes which appear to be devoid of lipophilic pocket L3. The presence of a 2'-fluorophenyl or 2'-nitrophenyl group at the C(5) position enhanced ligand affinity for the receptors but favored α1β3γ2 subtypes over α5β3γ2 subtypes. Replacement of the 2'- fluorophenyl or 2'-nitrophenyl group with a phenyl, 2'-thienyl or 2'-furyl moiety at the same position resulted in lower affinities of the ligands at all GABA(A) subtypes. Most importantly, when the carbonyl groups at position- 2 were replaced by methylene moieties (21 and 23), the affinities for all subtypes diminished. These results strongly suggest that the hydrogen bonding interaction of the ligand at H1 (as well as H2) with the receptor protein is important for high affinity at all DS sites. This implies that H1 is very similar in all receptor isoforms and may not be a descriptor which will readily lend itself to pharmacological receptor subtype selectivity.
- Yu, Shu,Ma, Chunrong,He, Xiaohui,McKernan, Ruth,Cook, James M.
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- Syntheses of 5-thienyl- and 5-furyl-substituted benzodiazepines: Probes of the pharmacophore for benzodiazepine receptor agonists
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The synthesis of 5-thienyl- and 5-furyl-substituted benzodiazepines is described. These compounds were employed to probe the lipophilic pocket (L3) of the benzodiazepine receptor (BzR) and to determine the effect of occupation of L3 on biological activity. Of the new analogs synthesized, the 5-(2-thienyl)-benzodiazepines 6a and 7a displayed high affinity for the BzR (IC50 28 and 18 nM, respectively) and exhibited both anticonvulsant (ED50 ~ 9 and 3 mg/kg) and muscle relaxant (ED50 ~ 10 and 7 mg/kg) activity. The 5-(3-thienyl)benzodiazepines 6d and 7d displayed only moderate affinity for the BzR (IC50 140 and 110 nM) and exhibited no biological activity (no anticonvulsant or muscle relaxant activity) at doses up to 40 mg/kg. The 5-(2-furyl)benzodiazepines (6b, 7b, 19b and 20b) exhibit low affinities for the BzR. These in vitro and in vivo findings are consistent with our model suggesting that pocket L3 is very sensitive to lipophilic effects. Thus, decreasing the lipophilicity of functional groups which occupy this region decreases ligand affinity at BzR. The 2'-halogen (F or Cl) substituent of the 5-phenylbenzodiazepines increases ligand affinity in vitro because the active conformation of the phenyl N(4)=C(5)-C(1')=C(2') moiety is syn rather than anti. The syn conformation permits the 2'-halogen (F or Cl) atom to interact at the hydrogen bonding site H2 and form a stable three-centered hydrogen bond in the proposed ligand binding cleft. The 3-thienyl and 2-furyl groups decrease the lipophilicity of the substituent which occupies L3 but do not form a hydrogen bond at H2, thus resulting in a diminished affinity at BzR.
- Zhang,Liu,Huang,Zhang,Koehler,Harris,Skolnick,Cook
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p. 483 - 496
(2007/10/02)
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