Search Results (31)

Brimonidine, a highly selective α₂-adrenergic receptor agonist originally developed for glaucoma treatment, has emerged as an important dermatological agent due to its potent vasoconstrictive and anti-inflammatory properties. This review summarizes its pharmacological characteristics, and clinical applications. By activating α₂-adrenergic receptors in cutaneous vessels, brimonidine induces rapid, reversible vasoconstriction and reduces neurogenic inflammation, leading to significant improvement of facial erythema in rosacea. Beyond its approved indication, topical brimonidine demonstrates efficacy in alcohol flushing syndrome, telangiectasia, post-procedural erythema, and as a local hemostatic agent in dermatologic surgery. Its favorable safety profile and minimal systemic absorption make it suitable for long-term use, though transient rebound erythema may occur. Advances in nanotechnology—such as supramolecular hydrogels and lipid-based carriers—enhance skin retention, prolong therapeutic action, and improve tolerability. These developments, together with ongoing synthesis of new quinoxaline–imidazoline analogues, open prospects for next-generation α₂-agonists with optimized selectivity and dermatologic applicability. Brimonidine’s emerging role extends to dermatologic formulations for transient redness and sensitive skin management. Integrating pharmacological, formulation, and molecular insights may transform brimonidine from a niche rosacea therapy into a versatile platform for vascular, inflammatory, and aesthetic skin treatments. Full article

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Because of its high potential for spreading and its limited response to treatment, UM remains a clinical challenge. Previous studies suggest that clinical adrenergic receptor (AR) antagonists might be effective in the treatment of UM. This study reports the antitumor activity of α-blocker in UM spheroids generated from α_1A- and α_2A-AR-positive UM cell lines. These cell lines were derived from primary tumors or hepatic metastases and differed in their genetic risk status for metastasis. Drug screening with UM spheroids revealed that prazosin and doxazosin dose-dependently reduced viability, whereas terazosin, alfuzosin, silodosin, tamsulosin, and phenoxybenzamine were found to be inefficient. Prazosin induced apoptosis, resulting in the disintegration of UM spheroid morphology and growth inhibition. Additionally, prazosin prevented UM spheroid cell outgrowth and long-term survival, indicating potential for tumor control. Like the selective α_1A-AR antagonist RS17053, prazosin inhibited the formation and growth of UM spheroids stimulated by the α_1-agonist phenylephrine. This suggests a tumor-preventive effect through the blockade of α_1A-AR. The present study highlights the responses of UM spheroids to α-AR antagonists and demonstrates that prazosin, doxazosin, or RS17053 may be a treatment option for preventing UM tumor recurrence or metastasis. Full article

Objective: This study was conducted to evaluate the potential radioprotective and therapeutic effects of dexmedetomidine (DEX), a selective α2-adrenergic receptor (α2AR) agonist, against ionizing X-ray-induced small intestinal injury in a dose-dependent manner. Methods: Male Sprague Dawley rats were randomly categorized into four groups. These groups were the Control, Ionizing Radiation (IR, 8 Gy X-ray), IR+DEX 100 µg/kg, and IR+DEX 200 µg/kg. DEX was administered intraperitoneally to the treatment groups 30 min before radiation exposure. All groups were sacrificed 24 h following irradiation. Firstly, the small intestinal tissues were evaluated histopathologically (H&E staining). Subsequently, levels of malondialdehyde (MDA) and glutathione (GSH), as markers of oxidative stress, were measured, and immunohistochemical expression of Caspase-3 and 8-hydroxy-2′-deoxyguanosine (8-OHdG) was analyzed. Results: In the IR group, significant histopathological alterations were observed, including villus atrophy and villus loss due to fusion, crypt loss, and mucosal degeneration. Additionally, there was an increase in MDA levels, a decrease in GSH levels, and a marked elevation in the expression of Caspase-3 and 8-OHdG. In the DEX-treated groups, particularly at the 200 µg/kg dose, significant improvements were noted in these parameters. It was determined that the histological architecture was largely preserved, oxidative stress was reduced, and apoptosis was suppressed. Conclusion: The findings suggest that DEX may effectively reduce X-ray-induced small intestinal injury in a dose-dependent manner, and that this effect is mediated through antioxidant and anti-apoptotic mechanisms. DEX holds potential for the prevention or treatment of radiation-induced gastrointestinal toxicities. Full article

Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) that partially reduce (20–50%) the contractile response to phenylephrine, suggesting that some ARBs may function as partial inverse agonists at αARs. Virtual ligand screening (docking) and molecular dynamics (MD) simulations were carried out to explore the binding affinities and stabilities of selected non-peptide ligands (e.g., ARBs and small-molecule opioids) for several G-protein coupled receptor (GPCR) types, including angiotensin II (AngII) type 1 receptor (AT₁R), α1AR, α2AR, and μ-(µOR) and ժ-opioid receptors (ժOR). Results: All ligands docked preferentially to the binding pocket on the cell surface domain of the GPCR types investigated. Drug binding was characterized by weak interactions (hydrophobic, hydrogen bonding, pi-pi) and stronger ionic and salt-bridge interactions (cation-pi and cation-anion interactions). Ligands specific to each GPCR category showed considerable cross-binding with alternative GPCRs, with small-molecule medications appearing less selective than their peptide or ARB functional equivalents. ARBs that exhibit higher affinities for AT₁R also demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone. Moreover, ARBs had a higher affinity for αARs than either alpha agonists (epinephrine and phenylephrine) or inhibitors (prazosin and doxazosin). MD simulations of membrane-embedded ARB-GPCR complexes proved stable over nanosecond time scales and suggested that some ARBs may behave as agonists or antagonists depending on the GPCR type. Based on the results presented in this and related investigations, we propose that agonists bind to the resting A-site of GPCRs, while inverse agonists occupy the desensitizing D-site, which partial agonists like morphine and fentanyl share, contributing to addiction. ARBs block both AngII and alpha receptors, suggesting that they are more potent antihypertensive drugs than ACE inhibitors. ARBs have the potential to inhibit morphine tolerance and appear to disrupt receptor desensitization processes, potentially by competing at the D-site. Our results suggest the possible therapeutic potential of ARBs in treating methamphetamine and opiate addictions. Full article

Backgrounds: Approximately 18 million individuals were diagnosed with cancer in 2018. The rate is predicted to exceed 22 million by 2030. Radiotherapy is an essential part of cancer therapy, with well documented local and systemic side effects, including oxidative stress and apoptosis. Kidney tissues are also exposed to the deleterious effects of radiotherapy, resulting in acute or chronic kidney function impairment. This study compared the effects of the potent selective α2-adrenoreceptor agonist dexmedetomidine and amifostine on oxidative stress and apoptosis in kidney damage induced by x-irradiation in rats. Methods: Forty Sprague Dawley rats were assigned into five groups: control, x-irradiation, x-irradiation + amifostine, x-irradiation + dexmedetomidine 100 µg/kg, and X-ray irradiation + dexmedetomidine 200 µg/kg. Results: Necrotic tubules and degenerative Bowman’s capsules were present in the x-irradiation group. An increase was determined in malondialdehyde (MDA), Cleaved Caspase-3, and 8-OHdG levels compared to the control group (p ≤ 0.05). In contrast, there was a decrease in necrotic tubules, degenerative Bowman’s capsules, and the levels of MDA, Cleaved Caspase-3, and 8-OHdG in the amifostine and dexmedetomidine 100 µg/kg and 200 µg/kg treatment groups (p ≤ 0.05). Conclusions: Alpha 2 adrenergic receptor agonists exhibit protective effects against kidney injury induced in association with x-irradiation by reducing oxidative stress and apoptosis. Full article

Background: Alterations in the adrenergic system have been associated with the pathophysiology of Alzheimer’s disease (AD). A novel α_1A-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 α_1A-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 α_1A-AR expression that was unaltered in the presence of cycloheximide or when performed at 37 °C. hAPP(lon) mice displayed a reduction in α_1A-AR-binding sites that were rescued upon prolonged incubation with CCF219B but also displayed a compensatory increase in α_1B/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’s ability to confer neuroprotection and be pro-cognitive in AD. CCF219B’s ability to increase the expression of α_1A-AR provides a positive feedback loop and strengthens the hypothesis that α₁-AR subtypes may be involved in AD etiology and/or progression. Full article

Surgical aortic valve replacement (SAVR) remains an essential treatment option for patients with aortic stenosis (AS). Open-heart surgery requires the use of cardiopulmonary bypass (CPB), which triggers an inflammatory response that can lead to end-organ dysfunction and severe complications. Dexmedetomidine, a highly selective α2-adrenergic agonist, is widely used in anesthesia and intensive care medicine for its sedative, analgesic, and sympatholytic properties. This study aimed to investigate whether dexmedetomidine exerts a clinically relevant anti-inflammatory effect in patients undergoing open-heart surgery and to determine the optimal dose. A prospective, double-blind, placebo-controlled study was conducted, including 60 patients randomized into three groups according to dexmedetomidine dose. Inflammatory markers (IL-6, TNF-α), renal function, and other clinical parameters were analyzed at multiple time points. Statistical analyses were performed to assess differences between the groups. Dexmedetomidine administration significantly affected TNF-α levels 12 h after CPB (p = 0.033), while previously reported suppression of IL-6 was not observed. Dexmedetomidine was associated with lower opioid consumption before extubation and showed a tendency to reduce postoperative delirium. Diuresis was significantly increased on the first postoperative day in dexmedetomidine-treated patients (p = 0.003), with no significant changes in other renal parameters. The incidence of atrial fibrillation was highest in the control group and lowest in the high-dose dexmedetomidine group, though this difference was not statistically significant. These results suggest that dexmedetomidine influences inflammatory and clinical outcomes; however, further research is needed to confirm its long-term benefits and optimal dosing strategies. Full article

Dexmedetomidine, a selective α2-adrenergic agonist, is favoured in intensive care for its minimal respiratory depression. This study evaluated the reporting frequency of rhabdomyolysis with dexmedetomidine compared to midazolam and propofol using the European pharmacovigilance database Eudravigilance. We conducted an observational, retrospective analysis of Individual Case Safety Reports (ICSRs) from 1 January 2013, to 31 December 2023. Primary and secondary outcomes included the reporting frequencies of rhabdomyolysis and its indicative signs and symptoms, respectively. We retrieved 19,268 ICSRs, of which 364 reported rhabdomyolysis associated with dexmedetomidine (3.8%), midazolam (10.2%), propofol (76.9%), or combinations thereof (9.1%). Dexmedetomidine showed a significantly lower reporting frequency of rhabdomyolysis compared to propofol (ROR, 0.32; 95% CI, 0.19–0.55) but no significant difference compared to midazolam. Subgroup analyses revealed higher frequencies in males, especially with propofol. Despite limitations such as underreporting, our findings suggest dexmedetomidine poses a lower rhabdomyolysis risk than propofol, supporting its safe use for sedation in high-risk patients. It is important to note that due to the retrospective design of this study our findings are indicative of correlations rather than causation. Continuous monitoring and further studies are recommended to validate these results. Full article

There is a preliminary record suggesting that β₂-adrenergic agonists may have therapeutic value in Parkinson’s disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study focuses on the importance of the prototypical β₂-adrenergic agonist epinephrine in relation to the incidence of Parkinson’s disease in humans, and its further investigation via synthetic selective β₂-receptor agonists, such as levalbuterol. Levalbuterol exerts significant anti-inflammatory activity, a property that may suppress cytokine-mediated degeneration of dopaminergic neurons and progression of Parkinsonism. In a completely novel finding, epinephrine and certain other adrenergic agents modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of anti-inflammatory glucocorticoids. This prompted in vivo confirmation in mice engrafted with human peripheral blood mononuclear cells (PBMCs). Upon toxic activation with mononuclear antibodies, levalbuterol inhibited (1) the release of the eosinophil attractant chemokine eotaxin-1, which is implicated in CNS and peripheral inflammatory disorders, (2) elaboration of the tumor-promoting angiogenic factor VEGFa, and (3) release of the pro-inflammatory cytokine IL-13 from activated PBMCs. These observations suggest possible translation to Parkinson’s disease, other neurodegenerative syndromes, and malignancies, via several mechanisms. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30% of patients experiencing persistent neuropathy for months or years after treatment cessation. An emerging potential intervention for the treatment of CIPN is cannabinoid-based pharmacotherapies. We have previously demonstrated that treatment with the psychoactive CB1/CB2 cannabinoid receptor agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC) or the non-psychoactive, minor phytocannabinoid cannabidiol (CBD) can attenuate paclitaxel-induced mechanical sensitivity in a mouse model of CIPN. We then showed that the two compounds acted synergically when co-administered in the model, giving credence to the so-called entourage effect. We and others have also demonstrated that CBD can attenuate several opioid-associated behaviors. Most recently, it was reported that another minor cannabinoid, cannabigerol (CBG), attenuated cisplatin-associated mechanical sensitivity in mice. Therefore, the goals of the present set of experiments were to determine the single and combined effects of cannabigerol (CBG) and cannabidiol (CBD) in oxaliplatin-associated mechanical sensitivity, naloxone-precipitated morphine withdrawal, and acute morphine antinociception in male C57BL/6 mice. Results demonstrated that CBG reversed oxaliplatin-associated mechanical sensitivity only under select dosing conditions, and interactive effects with CBD were sub-additive or synergistic depending upon dosing conditions too. Pretreatment with a selective α2-adrenergic, CB1, or CB2 receptor selective antagonist significantly attenuated the effect of CBG. CBG and CBD decreased naloxone-precipitated jumping behavior alone and acted synergistically in combination, while CBG attenuated the acute antinociceptive effects of morphine and CBD. Taken together, CBG may have therapeutic effects like CBD as demonstrated in rodent models, and its interactive effects with opioids or other phytocannabinoids should continue to be characterized. Full article

Pre-workout supplements are popular among sport athletes and overweight individuals. Phenethylamines (PEAs) and alkylamines (AA) are widely present in these supplements. Although the health effects of these analogues are not well understood yet, they are hypothesised to be agonists of adrenergic (ADR) and trace amine-associated receptors (TAARs). Therefore, we aimed to pharmacologically characterise these compounds by investigating their activating properties of ADRs and TAAR1 in vitro. The potency and efficacy of the selected PEAs and AAs was studied by using cell lines overexpressing human ADRα_1A/α_1B/α_1D/α_2a/α_2B/β₁/β₂ or TAAR1. Concentration–response relationships are expressed as percentages of the maximal signal obtained by the full ADR agonist adrenaline or the full TAAR1 agonist phenethylamine. Multiple PEAs activated ADRs (EC₅₀ = 34 nM–690 µM; E_max = 8–105%). Almost all PEAs activated TAAR1 (EC₅₀ = 1.8–92 µM; E_max = 40–104%). Our results reveal the pharmacological profile of PEAs and AAs that are often used in food supplements. Several PEAs have strong agonistic properties on multiple receptors and resemble potencies of the endogenous ligands, indicating that they might further stimulate the already activated sympathetic nervous system in exercising athletes via multiple mechanisms. The use of supplements containing one, or a combination of, PEA(s) may pose a health risk for their consumers. Full article

The α_2A adrenergic receptor (α_2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α_2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α_2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α_2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 μM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α_2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were −45.93 and −71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics. Full article

Rosacea is a common chronic inflammatory skin disorder that mainly affects the central face. It is primarily characterized by recurrent episodes of flushing, persistent erythema, inflammatory papules, telangiectasias, phymatous changes, and ocular symptoms. Its pathogenesis is complex and still not completely understood. It encompasses innate and adaptive immune system dysregulation, neurovascular dysfunction, and genetic and environmental factors. To date, four subtypes of rosacea have been identified, based on the predominant clinical features: erythemato-teleangiectatic, papulopustular, pyhomatous, and ocular rosacea. New insights into this condition have led to several pharmacological treatments, including topical medications, spanning from the conventional azelaic acid, metronidazole, benzoyl peroxide, clindamycin, and erythromycin to new ones including not only brimonidine, oxymetazoline, ivermectine, and minocycline but also systemic drugs such as oral antibiotics, isotretinoin, non-selective β-blockers or α2-adrenergic agonists, and laser- or light-based therapies, together with new therapeutic approaches. The aim of this study was to review the current literature on the pathophysiology of rosacea and to provide an overview of therapeutic approaches that specifically address each clinical subtype. Full article

The administration of the α₂-adrenergic receptor agonist clonidine via intracerebroventricular route produces hypotension in pentobarbital-anesthetized rats and pressor responses in conscious normotensive rats. We explored the impact of different anesthetics on the central nervous system-dependent cardiovascular effects of clonidine. Normotensive male Wistar rats with guide cannulas previously implanted in the cerebroventricular system were anesthetized with pentobarbital or ketamine/xylazine and prepared for blood pressure measurement. The animals received intracerebroventricular injections of 10 μg clonidine or 0.6 μg dexmedetomidine, and the effects on the systolic, diastolic, mean arterial pressure, and heart rate were evaluated. The influence of 5 μg yohimbine, a selective α₂-adrenergic receptor antagonist, was also assessed. The i.c.v. microinjection of clonidine decreased all three components of systemic arterial pressure and the heart rate of pentobarbital-anesthetized rats. On the other hand, clonidine increased the blood pressure and generated a less intense reduction in the heart rate of ketamine/xylazine-anesthetized rats. The pressor and bradycardic effects of clonidine in ketamine/xylazine-anesthetized animals were reproduced by dexmedetomidine, a more selective α₂-adrenergic receptor agonist. Notably, the previous intracerebroventricular injection of yohimbine significantly inhibited the hypertensive effect of clonidine and dexmedetomidine. This study discloses that while normotensive rats anesthetized with pentobarbital show hypotensive responses, the stimulation of α₂-adrenergic receptors increases the blood pressure in rats under ketamine/xylazine-induced anesthesia, reproducing the effects seen in conscious normotensive animals. Recognizing the mechanisms involved in these differences may allow us to understand better the final effects of clonidine and other α₂-adrenergic receptor agonists in the central nervous system, contributing to the repurposing of these drugs. Full article

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 α_1A-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. Full article