FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3008599973> ?p ?o ?g. }

• W3008599973 endingPage "350" @default.
• W3008599973 startingPage "336" @default.
• W3008599973 abstract "Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in preclinical and clinical studies. Their therapeutic window is narrow, however, and clinical application will likely only occur if greater discrimination in activity is achieved. Toward that end, we compared the modulatory activity of two PAMs recently considered as clinical candidates, LY451395 (mibampator) and PF-04958242/BIIB104, on recombinant and native AMPA receptors (AMPARs). We found that the principle molecular determinant that shaped modulatory activity of both PAMs on deactivation (recombinant) and decay (synaptic) of AMPARs was the auxiliary protein incorporated into the receptor complexes. AMPARs containing the stargazin/<i>γ</i>2 transmembrane AMPAR regulatory protein (TARP) were slowed to a >10-fold degree by both PAMs as compared with those incorporating <i>γ</i>8 TARP. Neither subunit composition nor flip/flop splice variation had substantive effect. Similarly, stargazin/<i>γ</i>2-containing mossy fiber EPSCs in cerebellar granule neurons were slowed to a ∼5-fold greater degree than EPSCs in hippocampal CA1 pyramidal cell neurons, which express the <i>γ</i>8 TARP. LY451395 exhibited greater efficacy than BIIB104 at both synapses. These studies provide insight into the receptor constituents that determine efficacy of sulfonamide PAMs. We conclude that compounds that discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/<i>γ</i>2 efficacy such as BIIB104, could act as viable procognitive therapeutics. <h3>SIGNIFICANCE STATEMENT</h3> Positive allosteric modulators (PAMs) of AMPA receptors enhance cognitive function in a variety of preclinical models. A clearer understanding of the critical determinants of PAM activity could yield critical insight into pathways to maximize their therapeutic index. Here we show that auxiliary proteins for AMPARs play a major, but thus far underappreciated, role in shaping recombinant and neuronal AMPAR modulation by two clinical candidate PAMs. These data will inform both clinical outcomes as well as future rational development of new modulators." @default.
• W3008599973 created "2020-03-06" @default.
• W3008599973 creator A5023213448 @default.
• W3008599973 creator A5044407567 @default.
• W3008599973 creator A5085869760 @default.
• W3008599973 date "2020-02-28" @default.
• W3008599973 modified "2023-10-10" @default.
• W3008599973 title "Auxiliary Proteins are the Predominant Determinants of Differential Efficacy of Clinical Candidates Acting as AMPA Receptor Positive Allosteric Modulators" @default.
• W3008599973 cites W1521933174 @default.
• W3008599973 cites W1965798600 @default.
• W3008599973 cites W1971449549 @default.
• W3008599973 cites W1973412317 @default.
• W3008599973 cites W1974716768 @default.
• W3008599973 cites W1986006987 @default.
• W3008599973 cites W1993536619 @default.
• W3008599973 cites W1997286443 @default.
• W3008599973 cites W2001638562 @default.
• W3008599973 cites W2003038730 @default.
• W3008599973 cites W2016288186 @default.
• W3008599973 cites W2016425978 @default.
• W3008599973 cites W2025704881 @default.
• W3008599973 cites W2027438525 @default.
• W3008599973 cites W2028185267 @default.
• W3008599973 cites W2034171869 @default.
• W3008599973 cites W2036313253 @default.
• W3008599973 cites W2038223805 @default.
• W3008599973 cites W2042678699 @default.
• W3008599973 cites W2044997440 @default.
• W3008599973 cites W2056194187 @default.
• W3008599973 cites W2063987809 @default.
• W3008599973 cites W2064629600 @default.
• W3008599973 cites W2065521724 @default.
• W3008599973 cites W2069644503 @default.
• W3008599973 cites W2080092700 @default.
• W3008599973 cites W2081659500 @default.
• W3008599973 cites W2084820245 @default.
• W3008599973 cites W2087262968 @default.
• W3008599973 cites W2088289750 @default.
• W3008599973 cites W2103218542 @default.
• W3008599973 cites W2106721061 @default.
• W3008599973 cites W2110892837 @default.
• W3008599973 cites W2116939117 @default.
• W3008599973 cites W2118223016 @default.
• W3008599973 cites W2139503851 @default.
• W3008599973 cites W2146332920 @default.
• W3008599973 cites W2152697634 @default.
• W3008599973 cites W2166223973 @default.
• W3008599973 cites W2592845471 @default.
• W3008599973 cites W2615999711 @default.
• W3008599973 cites W2731059737 @default.
• W3008599973 cites W2738417757 @default.
• W3008599973 cites W2765317118 @default.
• W3008599973 cites W2942750287 @default.
• W3008599973 cites W2952133564 @default.
• W3008599973 doi "https://doi.org/10.1124/mol.119.118554" @default.
• W3008599973 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32111699" @default.
• W3008599973 hasPublicationYear "2020" @default.
• W3008599973 type Work @default.
• W3008599973 sameAs 3008599973 @default.
• W3008599973 citedByCount "11" @default.
• W3008599973 countsByYear W30085999732020 @default.
• W3008599973 countsByYear W30085999732021 @default.
• W3008599973 countsByYear W30085999732022 @default.
• W3008599973 countsByYear W30085999732023 @default.
• W3008599973 crossrefType "journal-article" @default.
• W3008599973 hasAuthorship W3008599973A5023213448 @default.
• W3008599973 hasAuthorship W3008599973A5044407567 @default.
• W3008599973 hasAuthorship W3008599973A5085869760 @default.
• W3008599973 hasBestOaLocation W30085999731 @default.
• W3008599973 hasConcept C160268369 @default.
• W3008599973 hasConcept C166342909 @default.
• W3008599973 hasConcept C169760540 @default.
• W3008599973 hasConcept C170493617 @default.
• W3008599973 hasConcept C185592680 @default.
• W3008599973 hasConcept C2776038425 @default.
• W3008599973 hasConcept C55493867 @default.
• W3008599973 hasConcept C61174792 @default.
• W3008599973 hasConcept C86803240 @default.
• W3008599973 hasConcept C95444343 @default.
• W3008599973 hasConcept C98274493 @default.
• W3008599973 hasConceptScore W3008599973C160268369 @default.
• W3008599973 hasConceptScore W3008599973C166342909 @default.
• W3008599973 hasConceptScore W3008599973C169760540 @default.
• W3008599973 hasConceptScore W3008599973C170493617 @default.
• W3008599973 hasConceptScore W3008599973C185592680 @default.
• W3008599973 hasConceptScore W3008599973C2776038425 @default.
• W3008599973 hasConceptScore W3008599973C55493867 @default.
• W3008599973 hasConceptScore W3008599973C61174792 @default.
• W3008599973 hasConceptScore W3008599973C86803240 @default.
• W3008599973 hasConceptScore W3008599973C95444343 @default.
• W3008599973 hasConceptScore W3008599973C98274493 @default.
• W3008599973 hasIssue "5" @default.
• W3008599973 hasLocation W30085999731 @default.
• W3008599973 hasLocation W30085999732 @default.
• W3008599973 hasOpenAccess W3008599973 @default.
• W3008599973 hasPrimaryLocation W30085999731 @default.
• W3008599973 hasRelatedWork W1584162107 @default.
• W3008599973 hasRelatedWork W2100024810 @default.

• next