Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor

Papay, Robert S.; Macdonald, Jonathan D.; Stauffer, Shaun R.; Perez, Dianne M.

doi:10.1016/j.crphar.2022.100142

Cited by 3 publications

(7 citation statements)

References 68 publications

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“…Cmpd-3 was synthesized by The Center of Therapeutic Discovery at the Cleveland Clinic and verified by LC-MS and NMR at 98 + % purity. Details on synthesis and characterization is published ( Papay et al, 2023 ).…”

Section: Methodsmentioning

confidence: 99%

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A PAM of the α1A-Adrenergic receptor rescues biomarker, long-term potentiation, and cognitive deficits in Alzheimer’s disease mouse models without effects on blood pressure

Papay

Stauffer

Perez

2023

Current Research in Pharmacology and Drug Discovery

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Section: Methodsmentioning

confidence: 99%

“…We previously published that Cmpd-3 potentiates NE-mediated cAMP signaling with no effects on NE-mediated IP release. There are also no effects on EPI-mediated signaling pathways ( Papay et al, 2023 ). This signal bias would target effects to the brain with reduced effects in peripheral functions, particularly in blood pressure.…”

Section: Introductionmentioning

confidence: 99%

A PAM of the α1A-Adrenergic receptor rescues biomarker, long-term potentiation, and cognitive deficits in Alzheimer’s disease mouse models without effects on blood pressure

Papay

Stauffer

Perez

2023

Current Research in Pharmacology and Drug Discovery

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“…However, there are currently no clinical trials underway, most likely due to the potential to increase blood pressure and the risk of stroke. The use of positive allosteric modulators (PAMs) for the α 1A -AR developed to treat Alzheimer’s disease [ 12 ] are currently in preclinical studies in mice and to assess potential benefits in heart failure.…”

Section: α 1a -Ar Agonistsmentioning

confidence: 99%

“…Another issue is the poor brain penetration of most of the current α 1 -AR agonists which limit their use in neurological conditions. The first PAM at the α 1 -ARs with high selectivity for the α 1A -AR subtype has been developed [ 12 ] that can cross the blood–brain barrier sufficiently enough to improve cognitive functions and modify disease in Alzheimer’s disease mouse models without increased blood pressure. This drug (i.e., Cmpd-3, Table 1 ) only activates the NE-bound receptor and can potentiate cAMP signaling without effects on IP-signaling.…”

Section: α 1a -Ar Agonistsmentioning

confidence: 99%

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α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

Perez

2023

IJMS

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α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

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Progress on the development of Class A GPCR‐biased ligands

Morales,

Scharf,

Bermudez

et al. 2024

British J Pharmacology

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Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR‐biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.

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Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor

Cited by 3 publications

References 68 publications

A PAM of the α1A-Adrenergic receptor rescues biomarker, long-term potentiation, and cognitive deficits in Alzheimer’s disease mouse models without effects on blood pressure

A PAM of the α1A-Adrenergic receptor rescues biomarker, long-term potentiation, and cognitive deficits in Alzheimer’s disease mouse models without effects on blood pressure

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

Progress on the development of Class A GPCR‐biased ligands

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