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Research ArticleNEUROPHARMACOLOGY

An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

G. R. Dawson, K. A. Maubach, N. Collinson, M. Cobain, B. J. Everitt, A. M. MacLeod, H. I. Choudhury, L. M. McDonald, G. Pillai, W. Rycroft, A. J. Smith, F. Sternfeld, F. D. Tattersall, K. A. Wafford, D. S. Reynolds, G. R. Seabrook and J. R. Atack
Journal of Pharmacology and Experimental Therapeutics March 2006, 316 (3) 1335-1345; DOI: https://doi.org/10.1124/jpet.105.092320
G. R. Dawson
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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K. A. Maubach
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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N. Collinson
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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M. Cobain
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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B. J. Everitt
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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A. M. MacLeod
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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H. I. Choudhury
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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L. M. McDonald
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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G. Pillai
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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W. Rycroft
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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A. J. Smith
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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F. Sternfeld
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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F. D. Tattersall
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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K. A. Wafford
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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D. S. Reynolds
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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G. R. Seabrook
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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J. R. Atack
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)
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Abstract

α5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABAA receptors containing an α1, α2, α3, or α5 subunit but has inverse agonist efficacy selective for the α5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABAA receptors containing an α5 subunit. In a mouse hippocampal slice model, α5IA significantly enhanced the θ burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that α5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, α5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice α5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, α5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABAA α5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

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Journal of Pharmacology and Experimental Therapeutics: 316 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 3
1 Mar 2006
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Research ArticleNEUROPHARMACOLOGY

An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

G. R. Dawson, K. A. Maubach, N. Collinson, M. Cobain, B. J. Everitt, A. M. MacLeod, H. I. Choudhury, L. M. McDonald, G. Pillai, W. Rycroft, A. J. Smith, F. Sternfeld, F. D. Tattersall, K. A. Wafford, D. S. Reynolds, G. R. Seabrook and J. R. Atack
Journal of Pharmacology and Experimental Therapeutics March 1, 2006, 316 (3) 1335-1345; DOI: https://doi.org/10.1124/jpet.105.092320

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Research ArticleNEUROPHARMACOLOGY

An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

G. R. Dawson, K. A. Maubach, N. Collinson, M. Cobain, B. J. Everitt, A. M. MacLeod, H. I. Choudhury, L. M. McDonald, G. Pillai, W. Rycroft, A. J. Smith, F. Sternfeld, F. D. Tattersall, K. A. Wafford, D. S. Reynolds, G. R. Seabrook and J. R. Atack
Journal of Pharmacology and Experimental Therapeutics March 1, 2006, 316 (3) 1335-1345; DOI: https://doi.org/10.1124/jpet.105.092320
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