Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor.

Thais Emanoelle T Pompeu, Fernando Monteiro do Monte, Barbara Bosier, Carlos A M Fraga, Eliezer J Barreiro, Ricardo Menegatti, Emmanuel Hermans, François Noël

Progress in neuro-psychopharmacology & biological psychiatry 2015 Oct 1

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In an attempt to better understand the molecular mechanism of action of the antipsychotic lead LASSBio-579 and of its main metabolite LQFM 037, the aim of this work was to evaluate their intrinsic activity and binding kinetics at the dopamine D2 receptor. In transfected HEK cells expressing the D2L receptor under an inducible promoter, LASSBio-579 and LQFM 037, but not clozapine, behaved as weak partial agonists in [(35)S]-GTPγS binding assays performed in optimized conditions previously shown to evidence the partial agonist profile of aripiprazole. Besides, data obtained in radioligand competition assays on rat striatal membranes suggested a rapid association to and dissociation from the D2-like receptors. Using the kinetic rate index based on the strategy of the dual-point competition association assay, we showed that our compounds share a similar kinetic profile with clozapine, distinct from the typical antipsychotic haloperidol. These two characteristics could contribute to the atypical-like profile observed after administration of LASSBio-579 to rodents, in models of positive and negative symptoms of schizophrenia. Copyright © 2015 Elsevier Inc. All rights reserved.

Citation

Thais Emanoelle T Pompeu, Fernando Monteiro do Monte, Barbara Bosier, Carlos A M Fraga, Eliezer J Barreiro, Ricardo Menegatti, Emmanuel Hermans, François Noël. Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor. Progress in neuro-psychopharmacology & biological psychiatry. 2015 Oct 1;62:1-6