WAY-100635 is a potent dopamine D4 receptor agonist

  title={WAY-100635 is a potent dopamine D4 receptor agonist},
  author={Benjamin Reed Chemel and Bryan L. Roth and Blaine N. Armbruster and Val J. Watts and David E. Nichols},
Rationale and objectivesWAY-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.MethodThe functional properties and binding affinities of WAY… 

Structural Insights into 5-HT1A/D4 Selectivity of WAY-100635 Analogues: Molecular Modeling, Synthesis, and in Vitro Binding

In silico investigations revealed two key interactions for the 5-HT1A/D4 selectivity of WAY-100635 and analogues and a hydrogen bond only found with the Ser 7.36 of D4 receptor appeared to be the key for a higher D4 affinity for newly synthesized aza analogues.

WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation

The results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D4 receptors.


Various chemical modifications of the WAY-100635 structure were carried out in order to improve its 5-HT 1A versus D 4 selectivity and decrease the selectivity of the acyl group.

5-HT1A receptor pharmacophores to screen for off-target activity of α1-adrenoceptor antagonists

The insights and knowledge gained through the development of the new 5-HT1A-R pharmacophores will greatly aid in the design and synthesis of derivatives of the lead compound, and allow the generation of more efficacious and selective ligands.

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D1 Receptor Catechol Agonists

The hypothesis that the decreased D1 activity of chroman analogs results from a ligand intramolecular hydrogen bond that impairs the ability of the catechol to engage the receptor is supported.

Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells.

The in-vitro profile of over 30 ligands at recombinant hD4.4 receptors indicates that, unlike conventional or 'atypical' antipsychotics, several 'third generation' agents display D4 receptor partial agonism that may be sufficient to influence physiological D4 receptors activity in vivo.

Differential Effects of M1 and 5-Hydroxytryptamine1A Receptors on Atypical Antipsychotic Drug-Induced Dopamine Efflux in the Medial Prefrontal Cortex

DA efflux in the mPFC induced by the atypical antipsychotic drugs clozapine, risperidone, and olanzapine is also mediated by M1 receptor stimulation and results suggest that the AC260584, NDMC-, and clozAPine-induced DA eff Lux in themPFC is mediated directly by mP FC M1 receptors.

Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy

Evaluated cell membranes show that CBD interacts with human 5-HT1A receptors of the hippocampus and temporal neocortex, and at low concentrations, the effect of CBD upon Gi/o protein activation is limited, however, at high concentrations, CBD acts as an inverse agonist of 5- HT1A receptor.



A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635.

Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents.

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

The results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of ‘functionally selective’ activation of D2 (and possibly D3)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors—particularly 5-HT receptor subtypes (5-HT1A, 5- HT2A).

The pharmacological characterization of a novel selective 5-hydroxytryptamine1A receptor antagonist, NAD-299.

NAD-299 competitively antagonized the 8-hydroxy-2-(di-n-propylamino)tetralin-induced 5-HT behavioral effects, hypothermia, corticosterone secretion and inhibition of passive avoidance behavior without causing any actions of their own.

Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors

Long-term agonist-induced sensitization of adenylate cyclase by the D4 receptor may involve mechanisms that do not contribute to short-term sensitization, implying a role for Gi/Go proteins in heterologous sensitization.

Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635.

Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system

Future research should be directed towards: improvement of the metabolic stability in primates; development of a fluorinated radioligand which can be produced in large quantities and production of a radioiodinated or technetium-labelled ligand for SPET.