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.

Lewy Body Dementia Association's Industry Advisory Council: proceedings of the second annual meeting.

Abstract: In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council's goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.

Enabling methods to identify allosteric modulators of receptor activity

Abstract: A method developed to identify receptor modulators, involving providing a mutant receptor, wherein said mutant receptor has a mutation that alters the activity of said mutant receptor compared to a wild type receptor; contacting said mutant receptor with a candidate compound; and determining whether said candidate compound modulates the activity of said mutant receptor.

Comparative Efficacy, Safety, Tolerability, and Effectiveness of Antipsychotics in The Treatment of Dementia-Related Psychosis (DRP): A Systematic Literature Review

Abstract: To evaluate the comparative efficacy, safety, tolerability, and effectiveness of atypical antipsychotics (AAPs) for the treatment of dementia related psychosis (DRP) in older adults. In this systematic literature review (SLR), we qualitatively synthesized evidence on the comparative efficacy (based on neuropsychiatric inventory), tolerability (weight gain), and safety (cerebrovascular adverse events [CVAE], cardiovascular events, mortality, somnolence, extrapyramidal symptoms [EPS]) of AAPs used to treat DRP. We also assessed effectiveness based on all-cause discontinuations and discontinuations due to lack of efficacy or adverse events (AE). Published articles from through March 2021 from PubMed, EMBASE, PsycINFO, and Cochrane databases evaluated. We included double-blind, active-comparator/placebo-controlled randomized trials, open-label trials, and observational studies. This qualitative synthesis included 51 eligible studies with sample size of 13,334 and mean age of 79.36 years. Risperidone, olanzapine, quetiapine, and aripiprazole demonstrated numerically small improvement in psychotic symptoms among patients with DRP. Somnolence was the most reported AE for all the AAPs, with weight gain and tardive dyskinesia more common with olanzapine and risperidone, respectively. These AAPs are associated with falls, EPS, cognitive declines, CVAE, and mortality. Aripiprazole and olanzapine had lower odds of discontinuation due to lack of efficacy, with olanzapine having greater discontinuation odds due to AEs. This SLR demonstrated that AAPs used off-label to treat DRP are associated with small numerical symptom improvement but with a high risk of AEs, including cognitive decline and potentially higher mortality. These results underscore the need for new treatments with a favorable benefit-risk profile for treating DRP.

Identification of the Antiarrhythmic Drugs Amiodarone and Lorcainide as Potent H3 Histamine Receptor Inverse Agonists

Abstract: Use of molecular pharmacology to reprofile older drugs discovered before the advent of recombinant technologies is a fruitful method to elucidate mechanisms of drug action, expand understanding of structure-activity relationships between drugs and receptors, and in some cases, repurpose approved drugs. The H3 histamine receptor is a G-protein-coupled receptor (GPCR) primarily expressed in the central nervous system where among many things it modulates cognitive processes, nociception, feeding and drinking behavior, and sleep/wakefulness. In binding assays and functional screens of the H3 histamine receptor, the antiarrhythmic drugs lorcainide and amiodarone were identified as potent, selective antagonists/inverse agonists of human and rat H3 histamine receptors, with relatively little or no activity at over 20 other monoamine GPCRs, including H1, H2, and H4 receptors. Potent antagonism of H3 receptors was unique to amiodarone and lorcainide of 20 antiarrhythmic drugs tested, representing six pharmacological classes. These results expand the pharmacophore of H3 histamine receptor antagonist/inverse agonists and may explain, in part, the effects of lorcainide on sleep in humans.

Functional enhancement of AT1R potency in the presence of the TPαR is revealed by a comprehensive 7TM receptor co-expression screen.

Abstract: Background Functional cross-talk between seven transmembrane (7TM) receptors can dramatically alter their pharmacological properties, both in vitro and in vivo. This represents an opportunity for the development of novel therapeutics that potentially target more specific biological effects while causing fewer adverse events. Although several studies convincingly have established the existence of 7TM receptor cross-talk, little is known about the frequencey and biological significance of this phenomenon. Methodology/Principal Findings To evaluate the extent of synergism in 7TM receptor signaling, we took a comprehensive approach and co-expressed 123 different 7TM receptors together with the angiotensin II type 1 receptor (AT1R) and analyzed how each receptor affected the angiotensin II (AngII) response. To monitor the effect we used integrative receptor activation/signaling assay called Receptor Selection and Amplification Technology (R-SAT). In this screen the thromboxane A2α receptor (TPαR) was the only receptor which significantly enhanced the AngII-mediated response. The TPαR-mediated enhancement of AngII signaling was significantly reduced when a signaling deficient receptor mutant (TPαR R130V) was co-expressed instead of the wild-type TPαR, and was completely blocked both by TPαR antagonists and COX inhibitors inhibiting formation of thromboxane A2 (TXA2). Conclusions/Significance We found a functional enhancement of AT1R only when co-expressed with TPαR, but not with 122 other 7TM receptors. In addition, the TPαR must be functionally active, indicating the AT1R enhancement is mediated by a paracrine mechanism. Since we only found one receptor enhancing AT1R potency, our results suggest that functional augmentation through 7TM receptor cross-talk is a rare event that may require specific conditions to occur.