Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders

NEUROPHARMACOLOGY

卷:128

Article

Bruns, Robert F.¹  Mitchell, Stephen N.²  Wafford, Keith A.²  Harper, Alex J.²  Shanks, Elaine A.²  Carter, Guy²  O'Neill, Michael J.²  Murray, Tracey K.²  Eastwood, Brian J.²  Schaus, John M.¹  Beck, James P.¹  Hao, Junliang¹  Witkin, Jeffrey M.¹  Li, Xia¹  Chernet, Eyassu¹  Katner, Jason S.¹  Wang, Hong¹  Ryder, John W.¹  Masquelin, Meghane E.¹  Thompson, Linda K.¹  Love, Patrick L.¹  Maren, Deanna L.¹  Falcone, Julie F.¹  Menezes, Michelle M.¹  Zhang, Linli³  Yang, Charles R.³  Svensson, Kjell A.¹ 

[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Lilly Res Lab, Erl Wood Manor, England

[3] Shanghai ChemPartner, Shanghai 201203, Peoples R China

关键词: D1 receptor;    Dopamine;    Eye-blink;    Positive allosteric modulator;    Potentiator;    Parkinson's disease;   

DOI  :  10.1016/j.neuropharm.2017.10.032

来源: Elsevier

【 摘 要 】

DETQ an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder. (C) 2017 Eli Lilly and Company. Published by Elsevier Ltd.

【 授权许可】

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