ACADIA Pharmaceuticals Inc.

About: ACADIA Pharmaceuticals Inc. is a company organization based out in San Diego, California, United States. It is known for research contribution in the topics: Pimavanserin & Receptor. The organization has 260 authors who have published 276 publications receiving 8418 citations.

Dissection of the cytoplasmic domains of cytokine receptors involved in STAT and Ras dependent proliferation

Abstract: Cytokine receptors have different signaling requirements which ultimately lead to various physiological responses. In an effort to precisely characterize the molecular determinants involved in the proliferative response mediated by cytokines, we examine dose-dependent proliferation of the βc (GM-CSF, IL-3, IL-5) and homodimeric (G-CSF, TPO) cytokine receptors. Here we report that all cytokine receptors tested activate mostly STAT3 and STAT5. While STAT3 had a positive effect on βc cytokine receptor dependent proliferation, STAT5 was strongly inhibitory. Similarly, G-CSF and TPO lead to activation of STAT3 and STAT5 but, unlike the βc cytokine receptors, both stimulated cellular growth. On the other hand, Ras activation was necessary for all receptor mediated proliferation with the exception of G-CSF R. Truncated mutants of the receptors intracellular domains were used to delineate the functional domains involved in JAK/STAT and Ras activation linked to cellular growth. For instance, we revealed a critical role for the specific alpha subunit of the βc receptors in triggering receptor activation, STAT3 stimulation and proliferation, while Ras activation originates from the distal intracellular portion of the βc subunit. Finally, we showed that proximal STAT activation is the triggering event of G-CSF and TPO receptor function.

Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization

Abstract: Retinoid X receptors (RXRs) play key roles in many physiological processes in both the periphery and central nervous system. In addition, RXRs form heterodimers with other nuclear receptors to exert their physiological effects. The nuclear receptor related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However, only a small number of RXR-heterodimer selective modulators are available, with limited chemical diversity. This work describes the synthesis, biochemical evaluation, and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRα-NURR1 heterodimers. Targeted modifications to the small molecule biaryl scaffold caused local RXRα side-chain disturbances and displacement of secondary structural elements upon ligand binding. This resulted in the repositioning of protein helices in the heterodimer interface of RXRα, alterations in homo- versus heterodimer formation, and modulation of activation function 2 (AF2). The data provide a rationale for the design of RXR ligands consisting of a highly conserved hydrophilic region, strongly contributing to the ligand affinity, and a variable hydrophobic region, which efficiently probes the effects of structural changes at the level of the ligand on co-regulator recruitment or the RXRα-NURR1 dimerization interface.

Derivatives of (R)-1,11-methyleneaporphine: synthesis, structure, and interactions with G-protein coupled receptors.

Abstract: The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.