Thomas, P.H., Sundaram, H., Krishek, B.J., Chazot, P.L., Xie, X., Bevan, P., Brocchini, S., Latham, C.J., Charlton, P., Moore, M., Lewis, S.J., Thornton, D.M., Stephenson, F.A. and Smart, T.G. (1997) Regulation of neuronal and recombinant GABA(A) receptor ion channels by xenovulene A, a natural product isolated from Acremonium strictum. Journal of Pharmacology and Experimental Therapeutics, 282 (2). pp. 513-520.
Full text not available from this repository.
Xenovulene A (XR368) is a natural product exhibiting little structural resemblance with classical benzodiazepines yet is able to displace high-affinity ligand binding to the benzodiazepine site of the gamma-aminobutyric acid (GABA)A receptor. We have characterized this compound and an associated congener (XR7009) by use of radioligand binding and electrophysiological methodologies with native neurons and the Xenopus oocyte expression system. Xenovulene A, and the more potent XR7009, inhibited [3H]flunitrazepam binding to rat forebrain with Ki values of 7 and 192 nM, and 1.7 and 42 nM, respectively, each site accounting for approximately 50% of the total specific binding. In cerebellar and spinal cord membranes, these ligands identified only single binding sites. These ligands demonstrated no intrinsic agonist activity at recombinant GABA(A) receptors comprising alpha1beta1gamma2S subunits expressed in Xenopus oocytes, yet at 1 microM both significantly potentiated the GABA-induced response and reduced the GABA EC50 from 10.9 (control) to 5.1 (Xenovulene A) or 2.7 microM (XR7009). The rank potency order for enhancement of the 10 microM GABA response is: XR7009 (EC50, 0.02 microM) > diazepam (0.03) > Xenovulene A (0.05) > flurazepam (0.17). The activity of XR368 and XR7009 was reduced by the benzodiazepine antagonist, flumazenil, and absent in receptors devoid of the gamma2 subunit. These agents exhibited receptor subtype selectivity because alpha3beta1gamma2S receptors were less sensitive to these compounds relative to alpha1 subunit-containing receptors, whereas alpha6beta1gamma2S receptors were completely insensitive. Potentiation of the response to GABA on native GABA(A) receptors in cortical neurons substantiates the profile of the novel structures of Xenovulene A and XR7009 as specific benzodiazepine agonists.
|Departments, units and centres:||Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry|
|Journal or Publication Title:||Journal of Pharmacology and Experimental Therapeutics|
|Deposited By:||Library Staff|
|Deposited On:||25 Nov 2011 15:18|
|Last Modified:||25 Nov 2011 15:18|
Item downloaded times since 25 Nov 2011 15:18.
Repository Staff Only: Item control page
School of Pharmacy Staff Only: Edit a copy to replace this item