α₁-Adrenergic Receptors (ARs) are G-protein Coupled Receptors (GPCRs) that regulate the sympathetic nervous system via the binding and activation of norepinephrine (NE) and epinephrine (Epi). α₁-ARs control various aspects of neurotransmission, cognition, cardiovascular functions as well as other organ systems. However, therapeutic drug development for these receptors, particularly agonists, has been stagnant due to unwanted effects on blood pressure regulation. We report the synthesis and characterization of the first positive allosteric modulator (PAM) for the α₁-AR based upon the derivation of the α_1A-AR selective imidazoline agonist, cirazoline. Compound 3 (Cmpd-3) binds the α_1A-AR with high and low affinity sites (0.13pM; 54 nM) typical of GPCR agonists, and reverts to a single low affinity site of 100 nM upon the addition of GTP. Comparison of Cmpd-3 versus other orthosteric α_1A-AR-selective imidazoline ligands reveal unique properties that are consistent with a type I PAM. Cmpd-3 is both conformationally and ligand-selective for the α_1A-AR subtype. In competition binding studies, Cmpd-3 potentiates NE-binding at the α_1A-AR only on the high affinity state of NE with no effect on the Epi-bound α_1A-AR. Moreover, Cmpd-3 demonstrates signaling-bias and potentiates the NE-mediated cAMP response of the α_1A-AR at nM concentrations with no effects on the NE-mediated inositol phosphate response. There are no effects of Cmpd-3 on the signaling at the α_1B- or α_1D-AR subtypes. Cmpd-3 displays characteristics of a pure PAM with no intrinsic agonist properties. Specific derivation of Cmpd-3 at the R1 ortho-position recapitulated PAM characteristics. Our results characterize the first PAM for the α₁-AR and holds promise for a first-in-class therapeutic to treat various diseases without the side effect of increasing blood pressure intrinsic to classical orthosteric agonists.

01 Apr 2022·British Journal of PharmacologyQ2 · MEDICINE

α‐Adrenoceptor stimulation attenuates melanoma growth in mice

Q2 · MEDICINE

Article

Author: Ascione, Barbara ; Fidanza, Stefano ; Macchia, Daniele ; Gabriele, Lucia ; Matarrese, Paola ; Marano, Giuseppe ; Stati, Tonino ; Catalano, Liviana ; Buoncervello, Maria ; Maccari, Sonia

Background and PurposeRecently, β‐adrenoceptor blockade has emerged as a potential strategy to inhibit melanoma growth. It remains to be ascertained whether β‐adrenoceptor stimulation by circulating catecholamines increases melanoma growth in mice.Experimental ApproachB16F10 melanoma‐bearing mice were used to evaluate effects of adrenaline and specific adrenoceptor (AR) ligands on tumour volume. AR expression and effects of AR ligands on cell viability, production of mitochondrial reactive oxygen species (mROS), and proliferation activity in B16F10 cells, were determined by biochemical analyses.Key ResultsReal‐time polymerase chain reaction (qPCR) analyses revealed that B16F10 cells express α1B‐, α2A‐, α2B‐ and β2‐ARs. We found that treatment with the α‐ and β‐AR agonist adrenaline or with the synthetic catecholamine isoprenaline, which selectively stimulates β‐ARs, did not affect melanoma growth. Conversely, adrenaline reduced tumour growth in mice cotreated with propranolol, a β1β2‐AR antagonist. Adrenaline had no effect in tumour‐bearing β1β2‐AR knockout mice, in which β1‐ and β2‐ARs are lacking, but it reduced tumour growth when co‐administered with propranolol suggesting that tumour β2‐ARs negatively regulate adrenaline antitumour activity. Additionally, we found that α1‐AR stimulation with cirazoline yielded a decrease in B16F10 melanoma size. These effects on melanoma growth were paralleled by reduced cell viability and proliferation activity as well as increased mROS production in α1‐AR‐stimulated B16F10 cells. Decreased viability, proliferation and mitochondrial function in B16F10 cells also occurred after α2‐AR stimulation by α2‐AR agonist ST91.Conclusions and ImplicationsIn the B16F10 melanoma model, stimulation of α‐AR subtypes yields in vivo and in vitro anticancer activity.

01 Nov 2021·Life SciencesQ3 · MEDICINE

Adrenergic α2 receptors are implicated in seizure-induced respiratory arrest in DBA/1 mice

Q3 · MEDICINE

Article

Author: Zhang, Rui ; Niu, Jianguo ; Tan, Zheren ; Feng, Hua-Jun

AIMSSudden unexpected death in epilepsy (SUDEP) is a serious and underestimated public health burden. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous studies demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission modulates S-IRA. However, it remains unclear which adrenoceptors are implicated in S-IRA in DBA/1 mice.MATERIALS AND METHODSNaïve DBA/1 mice exhibit a low incidence of S-IRA, but after primed by acoustic stimulation, they become consistently susceptible to S-IRA. Atomoxetine, adrenoceptor agonists, antagonists or vehicle was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on S-IRA incidence and seizure behaviors were examined.KEY FINDINGSThe incidence of S-IRA in primed DBA/1 mice was significantly reduced by clonidine, an α2 adrenoceptor agonist, as compared with that of the vehicle control. However, compared with the vehicle control, S-IRA was not altered by cirazoline, an α1 agonist. Consistent with previous reports, atomoxetine reduced S-IRA in primed DBA/1 mice. The suppressing effect of atomoxetine on S-IRA was prevented by injection of an α2 adrenoceptor antagonist, yohimbine or atipamezole, but not by prazosin, an α1 antagonist. Administration of α1 or α2 antagonists alone did not promote the incidence of S-IRA in nonprimed DBA/1 mice.SIGNIFICANCEThese data demonstrate that noradrenergic neurotransmission modulates S-IRA predominantly via α2 adrenoceptors in DBA/1 mice, indicating that selective activation of α2 adrenoceptors can potentially prevent SUDEP.

100 Deals associated with Cirazoline

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KEGG	Wiki	ATC	Drug Bank
-	Cirazoline	-	DB09202

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Indication	Highest Phase	Country/Location	Organization	Date
Hypotension	Preclinical	IE	Smithkline Beecham Pharmaceuticals Ltd.	01 Oct 1992

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