Psychopharmacology

, Volume 188, Issue 2, pp 244–251

WAY-100635 is a potent dopamine D4 receptor agonist

  • Benjamin R. Chemel
  • Bryan L. Roth
  • Blaine Armbruster
  • Val J. Watts
  • David E. Nichols
Original Investigation

DOI: 10.1007/s00213-006-0490-4

Cite this article as:
Chemel, B.R., Roth, B.L., Armbruster, B. et al. Psychopharmacology (2006) 188: 244. doi:10.1007/s00213-006-0490-4

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.

Keywords

WAY-100635WAY-1006345-HT1AD4D2Receptor selectivity

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Benjamin R. Chemel
    • 1
  • Bryan L. Roth
    • 2
  • Blaine Armbruster
    • 2
  • Val J. Watts
    • 1
  • David E. Nichols
    • 1
  1. 1.Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical SciencesPurdue UniversityWest LafayetteUSA
  2. 2.Departments of BiochemistryPsychiatry, Neurosciences and NIMH Psychoactive Drug Screening Program, Case Western Reserve University Medical SchoolClevelandUSA