Research article summary (published 15 Aug 2006):

WAY-100635 is a potent dopamine D4 receptor agonist.

Full Abstract

RATIONALE AND OBJECTIVES: WAY-100635 is a prototypical 5-HT1A receptor antagonist and has been used widely as a pharmacological probe to investigate the distribution and function of 5-HT1A receptors. Results from our studies suggested that WAY-100635 was potently inducing effects unrelated to its 5-HT1A receptor affinity. In the present work, we evaluated the in vitro pharmacology of this compound at two D2-like receptor subtypes. METHOD: The functional properties and binding affinities of WAY-100635 were evaluated in HEK 293 cells stably expressing dopamine D2L or D4.4 receptors. RESULTS: Initial screens performed by the NIMH Psychoactive Drug Screening Program indicated that WAY-100635 displayed 940, 370, and 16 nM binding affinities at D2L, D3, and D4.2 receptors, respectively. Subsequent saturation analyses demonstrated that the Kd of [3H]WAY-100635 at D4.2 receptors was 2.4 nM, only tenfold higher than 5-HT1A. WAY-100635 and its major metabolite, WAY-100634, were potent agonists in HEK-D4.4 cells (EC50=9.7+/-2.2 and 0.65+/-0.2 nM, respectively). WAY-100635 behaved as a full agonist, and WAY-100634 was a nearly full agonist. In HEK-D2L cells, WAY-100635 weakly antagonized the effects of 300 nM quinpirole. Subsequent radioligand binding studies confirmed that WAY-100635 possesses high affinity for D4.4 receptors but binds weakly to D2L receptors (3.3+/-0.6 and 420+/-11 nM, respectively). CONCLUSIONS: This study demonstrates that WAY-100635 is not a "selective" 5-HT1A receptor antagonist, as previously reported, and conclusions drawn from studies that employed WAY-100635 as a selective 5-HT1A antagonist may need to be reevaluated.

Author information

Author/s: Chemel, Benjamin R (BR); Roth, Bryan L (BL); Armbruster, Blaine (B); Watts, Val J (VJ); Nichols, David E (DE);

Affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091, USA.

Grants: C06-14499 (Agency:PHS HHS) ; DA02189 (Agency:NIDA NIH HHS) ; K02MH01366 (Agency:NIMH NIH HHS) ; MH60397 (Agency:NIMH NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Psychopharmacology (Psychopharmacology (Berl)), published in Germany. (Language: eng)

Reference: 2006-Oct; vol 188 (issue 2) : pp 244-51

Dates: Created 2006/09/08; Completed 2007/01/17; Revised 2007/12/03;

PMID: 16915381, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Binding, Competitive CHO Cells Cricetinae Cricetulus Cyclic AMP - metabolism

Dopamine Agonists - pharmacology Humans Piperazines - pharmacology Pyridines - pharmacology Radioligand Assay Receptors, Dopamine D4 - agonists

Associated Chemicals: Dopamine Agonists (0) ; Piperazines (0) ; Pyridines (0) ; Receptors, Dopamine D4 (137750-34-6) ; WAY 100635 (146714-97-8) ; Cyclic AMP (60-92-4)

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