Article date: October 1993
By: Wha Bin Im, Haesook K. Im, Jeffrey F. Pregenzer, Beverly J. Hamilton, Donald B. Carter, E. Jon Jacobsen, Ruth E. TenBrink, Philip F. VonVoigtlander, in Volume 110, Issue 2, pages 677-680
In this study, we compared two series of newly discovered ligands for their selectivity to benzodiazepine sites in the α1β2γ2 and the α6β2γ2 subtypes of cloned γ‐aminbutyric acidA (GABAA) receptors, the latter being unique in not interacting with classical benzodiazepines.
The prototype compounds, U‐85575 (12‐chloro‐5‐(5‐cyclopropyl‐1′,2′,4′‐oxadiazol‐3′‐yl)‐2,3‐dihydro‐diimidazo[1,5‐a;1,2‐c]quinazoline), and U‐92330 (5‐acetyl‐3‐(5′‐cyclopropyl‐1′,2′,4′‐oxadiazole‐3′‐yl)‐7‐chloro‐4,5‐dihydro[1,5‐a]quinoxaliné), appear to share an overlapping recognition site with classical benzodiazepines on the GABAA receptor, because their potentiation of GABA‐mediated Cl− currents in both subtypes were sensitive to Ro 15–1788, a classical benzodiazepine antagonist.
Minor changes in the ring substituents of the drugs reduced their affinity to the α6β2γ2 subtype more pronouncedly than to the α1β2γ2 subtype. The diimidazoquinazoline containing a 2‐methyl group which projected below the plane of the rigid ring showed a markedly lower affinity to the α6β2γ2 subtype as compared to its stereoisomer having the methyl group above the plane of the ring. Also, the dihydroimidazoquinoxalines containing the 5‐benzoyl group showed a lower affinity to the α6β2γ2 subtype than the 5‐acetyl counterpart. In particular, the 5‐benzoyl analogue containing a 6‐fluoro group showed no interaction with the α6β2γ2 subtype even at the concentration of 10 μm, probably due to stabilization of the benzoyl group in the out‐of‐plane region by the steric and electrostatic effects of the 6‐fluoro group.
We propose that the benzodiazepine site of the α6β2γ2 subtype shares overlapping regions with that of the α1β2γ2 subtype, but has a sterically restricted out‐of‐plane region, which may be also incompatible with the 5‐phenyl group of classical benzodiazepines.
In this study, we compared two series of newly discovered ligands for their selectivity to benzodiazepine sites in the α1β2γ2 and the α6β2γ2 subtypes of cloned γ‐aminbutyric acidA (GABAA) receptors, the latter being unique in not interacting with classical benzodiazepines.
The prototype compounds, U‐85575 (12‐chloro‐5‐(5‐cyclopropyl‐1′,2′,4′‐oxadiazol‐3′‐yl)‐2,3‐dihydro‐diimidazo[1,5‐a;1,2‐c]quinazoline), and U‐92330 (5‐acetyl‐3‐(5′‐cyclopropyl‐1′,2′,4′‐oxadiazole‐3′‐yl)‐7‐chloro‐4,5‐dihydro[1,5‐a]quinoxaliné), appear to share an overlapping recognition site with classical benzodiazepines on the GABAA receptor, because their potentiation of GABA‐mediated Cl− currents in both subtypes were sensitive to Ro 15–1788, a classical benzodiazepine antagonist.
Minor changes in the ring substituents of the drugs reduced their affinity to the α6β2γ2 subtype more pronouncedly than to the α1β2γ2 subtype. The diimidazoquinazoline containing a 2‐methyl group which projected below the plane of the rigid ring showed a markedly lower affinity to the α6β2γ2 subtype as compared to its stereoisomer having the methyl group above the plane of the ring. Also, the dihydroimidazoquinoxalines containing the 5‐benzoyl group showed a lower affinity to the α6β2γ2 subtype than the 5‐acetyl counterpart. In particular, the 5‐benzoyl analogue containing a 6‐fluoro group showed no interaction with the α6β2γ2 subtype even at the concentration of 10 μm, probably due to stabilization of the benzoyl group in the out‐of‐plane region by the steric and electrostatic effects of the 6‐fluoro group.
We propose that the benzodiazepine site of the α6β2γ2 subtype shares overlapping regions with that of the α1β2γ2 subtype, but has a sterically restricted out‐of‐plane region, which may be also incompatible with the 5‐phenyl group of classical benzodiazepines.
DOI: 10.1111/j.1476-5381.1993.tb13864.x
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