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6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site.
Neuropharmacology. 2007 Sep; 53(4):574-82.N

Abstract

Neuroactivity of a number of flavonoids is mediated by modulation of type A gamma-aminobutyric acid (GABA(A)) receptor function via benzodiazepine sites, mostly as partial agonists. In the present study, 6,2'-dihydroxyflavone (DHF) was characterized for potential inverse agonistic activity, and its mechanism of action was explored for receptor subtype selectivity. In whole-cell patch clamp studies on neuroblastoma IMR-32 cells expressing native GABA(A) receptors, DHF decreased GABA-induced currents, to an extent similar to that induced by the partial inverse agonist FG-7142, which could be blocked by flumazenil, a BZ site antagonist. In mouse behavioral models, DHF elicited significant anxiogenic-like effects in the elevated plus-maze test, and enhanced cognitive performance in the step-through passive avoidance test, as expected for an inverse agonist. However, DHF did not exhibit any proconvulsant effects, a typical action of inverse agonists. In electrophysiological studies on subtypes of recombinant GABA(A) receptors expressed in HEK 293T cells, DHF decreased GABA-induced currents in alpha(1)beta(3)gamma(2), alpha(2)beta(3)gamma(2), or alpha(5)beta(3)gamma(2), but not alpha(3)beta(3)gamma(2) receptors. The results demonstrated DHF as a partial inverse agonist-like modulator of GABA(A) receptors with selectivity in receptor subtypes as well as behavioral effects. The DHF subtype-selectivity suggested that alpha(3)-containing subtypes could be a mediator of the convulsion activities of GABA(A) receptor inverse agonists. Moreover, the pharmacological profile displayed in mouse behavioral models supported DHF as a useful lead compound for the development of cognition-enhancing agents devoid of convulsion side effects.

Authors+Show Affiliations

Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17681556

Citation

Wang, Feng, et al. "6,2'-Dihydroxyflavone, a Subtype-selective Partial Inverse Agonist of GABAA Receptor Benzodiazepine Site." Neuropharmacology, vol. 53, no. 4, 2007, pp. 574-82.
Wang F, Xu Z, Yuen CT, et al. 6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site. Neuropharmacology. 2007;53(4):574-82.
Wang, F., Xu, Z., Yuen, C. T., Chow, C. Y., Lui, Y. L., Tsang, S. Y., & Xue, H. (2007). 6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site. Neuropharmacology, 53(4), 574-82.
Wang F, et al. 6,2'-Dihydroxyflavone, a Subtype-selective Partial Inverse Agonist of GABAA Receptor Benzodiazepine Site. Neuropharmacology. 2007;53(4):574-82. PubMed PMID: 17681556.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site. AU - Wang,Feng, AU - Xu,Zhiwen, AU - Yuen,Chun Tak, AU - Chow,Chui Yin, AU - Lui,Yuk Long, AU - Tsang,Shui Ying, AU - Xue,Hong, Y1 - 2007/06/30/ PY - 2007/04/10/received PY - 2007/06/04/revised PY - 2007/06/21/accepted PY - 2007/8/8/pubmed PY - 2007/12/21/medline PY - 2007/8/8/entrez SP - 574 EP - 82 JF - Neuropharmacology JO - Neuropharmacology VL - 53 IS - 4 N2 - Neuroactivity of a number of flavonoids is mediated by modulation of type A gamma-aminobutyric acid (GABA(A)) receptor function via benzodiazepine sites, mostly as partial agonists. In the present study, 6,2'-dihydroxyflavone (DHF) was characterized for potential inverse agonistic activity, and its mechanism of action was explored for receptor subtype selectivity. In whole-cell patch clamp studies on neuroblastoma IMR-32 cells expressing native GABA(A) receptors, DHF decreased GABA-induced currents, to an extent similar to that induced by the partial inverse agonist FG-7142, which could be blocked by flumazenil, a BZ site antagonist. In mouse behavioral models, DHF elicited significant anxiogenic-like effects in the elevated plus-maze test, and enhanced cognitive performance in the step-through passive avoidance test, as expected for an inverse agonist. However, DHF did not exhibit any proconvulsant effects, a typical action of inverse agonists. In electrophysiological studies on subtypes of recombinant GABA(A) receptors expressed in HEK 293T cells, DHF decreased GABA-induced currents in alpha(1)beta(3)gamma(2), alpha(2)beta(3)gamma(2), or alpha(5)beta(3)gamma(2), but not alpha(3)beta(3)gamma(2) receptors. The results demonstrated DHF as a partial inverse agonist-like modulator of GABA(A) receptors with selectivity in receptor subtypes as well as behavioral effects. The DHF subtype-selectivity suggested that alpha(3)-containing subtypes could be a mediator of the convulsion activities of GABA(A) receptor inverse agonists. Moreover, the pharmacological profile displayed in mouse behavioral models supported DHF as a useful lead compound for the development of cognition-enhancing agents devoid of convulsion side effects. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/17681556/62'_Dihydroxyflavone_a_subtype_selective_partial_inverse_agonist_of_GABAA_receptor_benzodiazepine_site_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(07)00194-3 DB - PRIME DP - Unbound Medicine ER -