{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:51Z","timestamp":1787029311072,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Aging","award":["RO1AG066627"],"award-info":[{"award-number":["RO1AG066627"]}]},{"name":"Alzheimer\u2019s Drug Discovery Foundation (ADDF)\u2014Program to Accelerate Clinical Trials (PACT)","award":["RO1AG066627"],"award-info":[{"award-number":["RO1AG066627"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Alterations in the adrenergic system have been associated with the pathophysiology of Alzheimer\u2019s disease (AD). A novel \u03b11A-adrenergic receptor (AR)-positive allosteric modulator (PAM), CCF219B, has been shown to outperform donepezil with rescue of AD cognition\/memory deficits with a reduction in amyloid biomarkers and without cardiovascular side effects. Initial pharmacological analysis in transfected cell lines revealed a signal bias with increased efficacy (but not potency) of cAMP signaling and ligand selectivity for norepinephrine (NE). As most GPCR allosteric modulators change the potency of agonists, we hypothesized and now report that CCF219B induced additional aspects of its allosteric interactions with NE that may provide mechanistic insight. Methods: Using Rat-1 fibroblasts stably transfected with \u03b11A-AR, we determined the activation profile of pERK and p38 messengers by CCF219B in the presence of NE. Using membranes prepared from the stably transfected fibroblasts or from the brain of WT mice or the AD mouse model, hAPP(lon), equilibrium or kinetic radioligand-binding analyses were performed. Results: We identified p-ERK1\/2 but not p38 as an additional signal pathway that is potentiated by CCF219B in the presence of NE. An analysis of binding studies of CCF219B in membranes derived from the brains of WT or hAPP(lon) mice revealed profiles that were time-dependent and resulted in an increase in \u03b11A-AR expression that was unaltered in the presence of cycloheximide or when performed at 37 \u00b0C. hAPP(lon) mice displayed a reduction in \u03b11A-AR-binding sites that were rescued upon prolonged incubation with CCF219B but also displayed a compensatory increase in \u03b11B\/D-AR subtype expression. Binding kinetics reveal that CCF219B can decrease the association rate of 3H-NE but only in the presence of GTP. The association rate increased for the radiolabeled antagonist, 125I-HEAT. There were no changes in the dissociation rate of either radiolabel. Conclusions: CCF219B affects the association but not the dissociation rate of NE and explains its ability to increase the active state of the receptor by promoting a pre-coupled conformation, consistent with increasing efficacy but not potency. Potentiation of pERK may contribute to CCF219B\u2019s ability to confer neuroprotection and be pro-cognitive in AD. CCF219B\u2019s ability to increase the expression of \u03b11A-AR provides a positive feedback loop and strengthens the hypothesis that \u03b11-AR subtypes may be involved in AD etiology and\/or progression.<\/jats:p>","DOI":"10.3390\/ph18040476","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T06:06:35Z","timestamp":1743141995000},"page":"476","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Further In Vitro and Ex Vivo Pharmacological and Kinetic Characterizations of CCF219B: A Positive Allosteric Modulator of the \u03b11A-Adrenergic Receptor"],"prefix":"10.3390","volume":"18","author":[{"given":"Robert S.","family":"Papay","sequence":"first","affiliation":[{"name":"The Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1790-5776","authenticated-orcid":false,"given":"Dianne M.","family":"Perez","sequence":"additional","affiliation":[{"name":"The Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Perez, D.M. (2020). \u03b11-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.581098"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0197-4580(83)90002-7","article-title":"Biochemical changes in Dementia disorders of Alzheimer type (AD\/SDAT)","volume":"4","author":"Gottfries","year":"1983","journal-title":"Neurobiol. Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/alzrt175","article-title":"Targeting norepinephrine in mild cognitive impairment and Alzheimer\u2019s disease","volume":"5","author":"Chalermpalanupap","year":"2013","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.neurobiolaging.2006.06.003","article-title":"Noradrenaline deficiency in brain increases \u03b2-amyloid plaque burden in an animal model of Alzheimer\u2019s disease","volume":"28","author":"Kalinin","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gannon, M., Che, P., Chen, Y., Jiao, K., Roberson, E.D., and Wang, Q. (2015). Noradrenergic dysfunction in Alzheimer\u2019s disease. Front. Neurosci., 9.","DOI":"10.3389\/fnins.2015.00220"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.brainres.2017.09.035","article-title":"Assessing disease-modifying effects of norepinephrine in Down syndrome and Alzheimer\u2019s disease","volume":"1702","author":"Ponnusamy","year":"2019","journal-title":"Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1093\/ijnp\/pyab006","article-title":"Noradrenergic Enhancement of Motor Learning, Attention, and Working Memory in Humans","volume":"24","author":"Kuo","year":"2021","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1124\/mol.111.073734","article-title":"Long-Term \u03b11A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity","volume":"80","author":"Doze","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.neuroscience.2007.01.031","article-title":"Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes","volume":"146","author":"Szot","year":"2007","journal-title":"Neuroscience"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s007020170065","article-title":"A study of alpha-adrenoceptor gene polymorphisms and Alzheimer disease","volume":"108","author":"Hong","year":"2001","journal-title":"J. Neural Transm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100142","DOI":"10.1016\/j.crphar.2022.100142","article-title":"Characterization of a novel positive allosteric modulator of the \u03b11A-Adrenergic receptor","volume":"4","author":"Papay","year":"2022","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100160","DOI":"10.1016\/j.crphar.2023.100160","article-title":"A PAM of the \u03b11A-Adrenergic receptor rescues biomarker, long-term potentiation, and cognitive deficits in Alzheimer\u2019s disease mouse models without effects on blood pressure","volume":"5","author":"Papay","year":"2023","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1111\/j.1532-5415.2009.02521.x","article-title":"High Blood Pressure and Microinfarcts: A Link Between Vascular Risk Factors, Dementia, and Clinical Alzheimer\u2019s Disease","volume":"57","author":"Schneider","year":"2009","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0092-8674(94)90401-4","article-title":"cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase","volume":"79","author":"Huang","year":"1994","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eade3380","DOI":"10.1126\/scisignal.ade3380","article-title":"Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for learning and memory","volume":"16","author":"Martinez","year":"2023","journal-title":"Sci. Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e15984","DOI":"10.15252\/emmm.202215984","article-title":"Nuclear ERK1\/2 signaling potentiation enhances neuroprotection and cognition via Importin\u03b11\/KPNA2","volume":"15","author":"Indrigo","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102346","DOI":"10.1016\/j.jchemneu.2023.102346","article-title":"Ginsenoside Rg2 alleviates neurovascular damage in 3xTg-AD mice with Alzheimer\u2019s disease through the MAPK-ERK pathway","volume":"133","author":"Ye","year":"2023","journal-title":"J. Chem. Neuroanat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1016\/j.bbamcr.2013.06.013","article-title":"The three \u03b11-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1\/2 phosphorylation","volume":"1833","author":"Segura","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/0006-2952(91)90290-L","article-title":"Estimation of the kinetic constants for binding of epinephrine to \u03b2-adrenergic receptors of the S49 cell","volume":"42","author":"Stickle","year":"1991","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0022-3565(25)24912-6","article-title":"Thermodynamic properties of agonist interactions with the beta adrenergic receptor-coupled adenylate cyclase system. II. Agonist binding to soluble beta adrenergic receptors","volume":"237","author":"Contreras","year":"1986","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/349704a0","article-title":"Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease","volume":"349","author":"Goate","year":"1991","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1093\/hmg\/ddu064","article-title":"The familial Alzheimer\u2019s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons","volume":"23","author":"Muratore","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.neurobiolaging.2007.06.011","article-title":"Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice","volume":"30","author":"Dewachter","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0026-895X(25)10258-7","article-title":"Characterization of alpha-1-adrenergic receptor subtypes in rat-brain\u2014A reevaluation of [3H]WB4104 and [3H]prazosin binding","volume":"29","author":"Morrow","year":"1986","journal-title":"Mol. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1111\/j.1476-5381.2009.00604.x","article-title":"Ligand binding assays at equilibrium: Validation and interpretation","volume":"161","author":"Hulme","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0161-5890(90)90045-2","article-title":"The effect of temperature on the binding kinetics and equilibrium constants of monoclonal antibodies to cell surface antigens","volume":"27","author":"Johnstone","year":"2002","journal-title":"Mol. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.bbagen.2015.10.010","article-title":"On the link between conformational changes, ligand binding and heat capacity","volume":"1860","author":"Vega","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA) Gen. Subj."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Perez, D.M. (2021). Current Developments on the Role of \u03b11-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.652152"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e030780","DOI":"10.1161\/JAHA.123.030780","article-title":"Cardiovascular Disease and Alzheimer\u2019s Disease: The Heart\u2013Brain Axis","volume":"12","author":"Saeed","year":"2023","journal-title":"J. Am. Hear. Assoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1111\/ejn.14735","article-title":"Norepinephrine stabilizes translation-dependent, homosynaptic long-term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK","volume":"52","author":"Maity","year":"2020","journal-title":"Eur. J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1101\/lm.039222.115","article-title":"Norepinephrine triggers metaplasticity of LTP by increasing translation of specific mRNAs","volume":"22","author":"Maity","year":"2015","journal-title":"Learn. Mem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.tips.2020.12.005","article-title":"Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery","volume":"42","author":"Slosky","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Albert-Gasc\u00f3, H., Ros-Bernal, F., Castillo-G\u00f3mez, E., and Olucha-Bordonau, F.E. (2020). MAP\/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124471"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1124\/pr.54.2.323","article-title":"G Protein-Coupled Receptor Allosterism and Complexing","volume":"54","author":"Christopoulos","year":"2002","journal-title":"Pharmacol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature18324","article-title":"Allosteric coupling from G protein to the agonist-binding pocket in GPCRs","volume":"535","author":"DeVree","year":"2016","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1016\/j.cell.2021.02.041","article-title":"Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling","volume":"184","author":"Huang","year":"2021","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41467-020-14526-3","article-title":"Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the \u03b21-adrenergic receptor","volume":"11","author":"Frei","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1038\/s41467-023-39310-x","article-title":"Structural basis of \u03b11A-adrenergic receptor activation and recognition by an extracellular nanobody","volume":"14","author":"Toyoda","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature12735","article-title":"Activation and allosteric modulation of a muscarinic acetylcholine receptor","volume":"504","author":"Kruse","year":"2013","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9474","DOI":"10.1073\/pnas.132552699","article-title":"Knockout of the \u03b11A\/C-adrenergic receptor subtype: The \u03b11A\/C is expressed in resistance arteries and is required to maintain arterial blood pressure","volume":"99","author":"Rokosh","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.molbrainres.2005.06.013","article-title":"\u03b11-Adrenoreceptor in human hippocampus: Binding and receptor subtype mRNA expression","volume":"139","author":"Szot","year":"2005","journal-title":"Mol. Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/cne.20992","article-title":"Localization of the mouse \u03b11A-adrenergic receptor (AR) in the brain: \u03b11AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors","volume":"497","author":"Papay","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.biopsych.2005.04.051","article-title":"Polymorphisms in the Promoter Region of the Alpha1A-Adrenoceptor Gene Are Associated with Schizophrenia\/Schizoaffective Disorder in a Spanish Isolate Population","volume":"58","author":"Clark","year":"2005","journal-title":"Biol. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s007020070005","article-title":"Subchronic treatment with prazosin improves passive avoidance learning in aged mice: Possible relationships to \u03b11 -receptor up-regulation","volume":"107","author":"Knauber","year":"2000","journal-title":"J. Neural Transm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5839","DOI":"10.1074\/jbc.271.10.5839","article-title":"\u03b11-Adrenergic Receptor Subtype mRNAs Are Differentially Regulated by \u03b11-Adrenergic and Other Hypertrophic Stimuli in Cardiac Myocytes in Culture and in Vivo","volume":"271","author":"Rokosh","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.cardiores.2003.09.020","article-title":"The \u03b11B-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model","volume":"60","author":"Ross","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1046\/j.1528-1157.2002.13202.x","article-title":"Systemic Overexpression of the \u03b11B-Adrenergic Receptor in Mice: An Animal Model of Epilepsy","volume":"43","author":"Kunieda","year":"2002","journal-title":"Epilepsia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/85124","article-title":"Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons","volume":"4","author":"Paladini","year":"2001","journal-title":"Nat. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1046\/j.1471-4159.2003.01867.x","article-title":"Alpha1B adrenergic receptor knockout mice are protected against methamphetamine toxicity","volume":"86","author":"Battaglia","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1046\/j.1471-4159.2002.01170.x","article-title":"Mice expressing the \u03b11B-adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation","volume":"83","author":"Papay","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1038\/82207","article-title":"Overexpression of the \u03b11B-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy","volume":"6","author":"Zuscik","year":"2000","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9675","DOI":"10.1007\/s11357-014-9675-7","article-title":"Long-term \u03b11B-adrenergic receptor activation shortens lifespan, while \u03b11A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence","volume":"36","author":"Collette","year":"2014","journal-title":"AGE"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1528-1167.2008.01972.x","article-title":"Lack of \u03b11b-adrenergic receptor protects against epileptic seizures","volume":"50","author":"Pizzanelli","year":"2009","journal-title":"Epilepsia"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Bekdash, R.A. (2021). The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031273"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1110\/ps.0240003","article-title":"Protein stability induced by ligand binding correlates with changes in protein flexibility","volume":"12","author":"Celej","year":"2003","journal-title":"Protein Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1124\/jpet.104.073767","article-title":"Regulation of M2 Muscarinic Acetylcholine Receptor Expression and Signaling by Prolonged Exposure to Allosteric Modulators","volume":"312","author":"May","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1021\/cn400005t","article-title":"Regulation of G Protein-Coupled Receptors by Allosteric Ligands","volume":"4","author":"Lane","year":"2013","journal-title":"ACS Chem. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1124\/mol.119.116772","article-title":"Calcium-Sensing Receptor Internalization Is \u03b2-Arrestin\u2013Dependent and Modulated by Allosteric Ligands","volume":"96","author":"Mos","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9517","DOI":"10.1074\/jbc.M609045200","article-title":"Rescue of Calcium-sensing Receptor Mutants by Allosteric Modulators Reveals a Conformational Checkpoint in Receptor Biogenesis","volume":"282","author":"Huang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1210\/en.2012-1887","article-title":"Impact of Clinically Relevant Mutations on the Pharmacoregulation and Signaling Bias of the Calcium-Sensing Receptor by Positive and Negative Allosteric Modulators","volume":"154","author":"Leach","year":"2013","journal-title":"Endocrinology"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/4\/476\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:03:23Z","timestamp":1760029403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/4\/476"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,27]]},"references-count":60,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ph18040476"],"URL":"https:\/\/doi.org\/10.3390\/ph18040476","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,27]]}}}