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Journal of Basic and Clinical... Jun 2021Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist...
OBJECTIVES
Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles.
METHODS
The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α-adrenoceptor antagonist prazosin was used as control.
RESULTS
Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.
CONCLUSIONS
Our data suggest that CCR antagonists should be screened for cross-reactivity with α-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Phenylephrine; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Chemokine; beta-Arrestins
PubMed: 34144642
DOI: 10.1515/jbcpp-2020-0523 -
Profiles of Drug Substances,... 2017Propranolol is a noncardioselective β-blocker. It is reported to have membrane-stabilizing properties, but it does not own intrinsic sympathomimetic activity....
Propranolol is a noncardioselective β-blocker. It is reported to have membrane-stabilizing properties, but it does not own intrinsic sympathomimetic activity. Propranolol hydrochloride is used to control hypertension, pheochromocytoma, myocardial infarction, cardiac arrhythmias, angina pectoris, and hypertrophic cardiomyopathy. It is also used to control symptoms of sympathetic overactivity in the management of hyperthyroidism, anxiety disorders, and tremor. Other indications cover the prophylaxis of migraine and of upper gastrointestinal bleeding in patients with portal hypertension. This study provides a detailed, comprehensive profile of propranolol, including formulas, elemental analysis, and the appearance of the drug. In addition, the synthesis of the drug is described. The chapter covers the physicochemical properties, including X-ray powder diffraction, pK, solubility, melting point, and procedures of analysis (spectroscopic, electrochemical, and chromatographic). In-depth pharmacology is also presented (pharmacological actions, therapeutic dosing, uses, Interactions, and adverse effects and precautions). More than 60 references are given as a proof of the abovementioned studies.
Topics: Adrenergic beta-Antagonists; Drug Stability; Humans; Hypertension; Molecular Structure; Propranolol
PubMed: 28431779
DOI: 10.1016/bs.podrm.2017.02.006 -
Autonomic Neuroscience : Basic &... Jun 2009It is necessary to note at very beginning, that up to now a comparative approach to the discussion of the structure and function of synthetic and endogenous... (Review)
Review
It is necessary to note at very beginning, that up to now a comparative approach to the discussion of the structure and function of synthetic and endogenous beta-adrenergic agonists for biomedical and clinical sciences does not appear to be available in the literature. Maybe, one of the reasons for this lies in the differential relations and constant attention of investigators either to the synthetic beta-adrenergic blockers on one hand or to endogenous beta-adrenergic receptor antagonists (EBARA) on the other. Therefore, the main goal of this article is to attempt to overcome this. It is clear now that there are several common properties and relevant features among synthetic beta-adrenergic receptor blockers, endogenous nonspecific beta-adrenergic antagonists (ENBARA) and relative endogenous specific beta-adrenergic antagonists (RESBARA). They are predominantly related to the reduction of adrenergic influence, namely, beta-adrenergic receptor neurotransmission, and, at an intracellular molecular level, to inhibition of adenylate cyclase and a decrease in cyclic AMP content. Other relevant and individual differences are also available and are also discussed.
Topics: Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-Antagonists; Animals; Humans; Receptors, Adrenergic, beta-2
PubMed: 19328045
DOI: 10.1016/j.autneu.2009.02.005 -
Survey of Ophthalmology 2006Understanding the role of adrenergic receptors in iris biology has gained widespread interest due to the recently described intraoperative floppy iris syndrome sometimes... (Review)
Review
Understanding the role of adrenergic receptors in iris biology has gained widespread interest due to the recently described intraoperative floppy iris syndrome sometimes encountered during cataract surgery. alpha(1)AR-mediated iris dilator smooth muscle contraction occurs via alpha(1a)ARs whereas alpha(1b)ARs mediate iris arteriolar contraction. Because alpha(1)AR antagonists are first-line therapy for benign prostatic hyperplasia and lower urinary tract symptoms, more elderly patients requiring cataract surgery now receive these drugs. After reviewing intraoperative floppy iris syndrome, strengths/weaknesses of supporting data, and reviewing iris biology, a case is made that rather than being drug specific (alpha(1)AR antagonists), intraoperative floppy iris syndrome may represent the "tip of the iceberg." Relaxed iris dilator muscle resistant to adrenergic agonists should be expected with clinical drugs shown to relax the iris dilator (e.g., antagonists at alpha(1)AR, endothelin-A, angiotensin receptors, nitric oxide donors such as nitrates), and/or diseases associated with endothelial dysregulation (e.g., congestive heart failure, diabetes, hypertension). Rather than a rare, unexpected, unpredictable syndrome due to one drug, a careful medical history should elucidate intraoperative floppy iris syndrome predisposition. Just as anticoagulants are discontinued prior to elective surgery, conservative management of elderly patients suggests discontinuation of drugs that relax iris dilator muscle, in consultation with the patient's primary physician, should be considered prior to cataract surgery.
Topics: Adrenergic Antagonists; Adrenergic alpha-1 Receptor Antagonists; Animals; Cataract Extraction; Humans; Intraoperative Complications; Iris; Iris Diseases; Male; Muscle Contraction; Muscle, Smooth; Prostatic Hyperplasia; Pupil; Receptors, Adrenergic, alpha-1; Syndrome; Urologic Diseases
PubMed: 16950249
DOI: 10.1016/j.survophthal.2006.06.011 -
Communications Biology Nov 2022Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission....
Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission. VMAT2 inhibitors are approved for symptomatic treatment of tardive dyskinesia and Huntington's chorea, but despite being much-studied inhibitors their exact binding site and mechanism behind binding and inhibition of monoamine transport are not known. Here we report the identification of several approved drugs, notably β2-adrenergic agonists salmeterol, vilanterol and formoterol, β2-adrenergic antagonist carvedilol and the atypical antipsychotic ziprasidone as inhibitors of rat VMAT2. Further, plausible binding modes of the established VMAT2 inhibitors reserpine and tetrabenazine and hit compounds salmeterol and ziprasidone were identified using molecular dynamics simulations and functional assays using VMAT2 wild-type and mutants. Our findings show VMAT2 as a potential off-target of treatments with several approved drugs in use today and can also provide important first steps in both drug repurposing and therapy development targeting VMAT2 function.
Topics: Animals; Rats; Adrenergic Agonists; Antipsychotic Agents; Piperazines; Vesicular Monoamine Transport Proteins; Adrenergic Antagonists
PubMed: 36418492
DOI: 10.1038/s42003-022-04121-1 -
Psychiatry Research Nov 2022Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from... (Review)
Review
Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from January 2011 to November 2021 were identified via PubMed and analyzed for evidence supporting changes. Following consideration of variations required by special patient populations, treatment of sleep impairments remains as the first recommended step. Nightmares and non-nightmare disturbed awakenings are best addressed with the anti-adrenergic agent prazosin, with doxazosin and clonidine as alternatives. First choices for difficulty initiating sleep include hydroxyzine and trazodone. If significant non-sleep PTSD symptoms remain, an SSRI should be tried, followed by a second SSRI or venlafaxine as a third step. Second generation antipsychotics can be considered, particularly for SSRI augmentation when PTSD-associated psychotic symptoms are present, with the caveat that positive evidence is limited and side effects are considerable. Anti-adrenergic agents can also be considered for general PTSD symptoms if not already tried, though evidence for daytime use lags that available for sleep. Regarding other pharmacological and procedural options, e.g., transcranial magnetic stimulation, cannabinoids, ketamine, psychedelics, and stellate ganglion block, evidence does not yet support firm inclusion in the algorithm. An interactive version of this work can be found at www.psychopharm.mobi.
Topics: Humans; Stress Disorders, Post-Traumatic; Psychopharmacology; Prazosin; Dreams; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Adrenergic Antagonists
PubMed: 36162349
DOI: 10.1016/j.psychres.2022.114840 -
The Journal of Experimental Biology Mar 2018The enormous plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. In energy... (Review)
Review
The enormous plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. In energy balance, lipolysis of triacylglycerols and re-esterification of free fatty acids are opposing processes operating in parallel at identical rates, thus allowing a more dynamic transition from anabolism to catabolism, and vice versa. In response to alterations in the state of energy balance, one of the two processes predominates, enabling the efficient mobilization or storage of energy in a negative or positive energy balance, respectively. The release of noradrenaline from the sympathetic nervous system activates lipolysis in a depot-specific manner by initiating the canonical adrenergic receptor-G-protein-adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A pathway, targeting proteins of the lipolytic machinery associated with the interface of the lipid droplets. In brown and brite adipocytes, lipolysis stimulated by this signaling pathway is a prerequisite for the activation of non-shivering thermogenesis. Free fatty acids released by lipolysis are direct activators of uncoupling protein 1-mediated leak respiration. Thus, pro- and anti-lipolytic mediators are bona fide modulators of thermogenesis in brown and brite adipocytes. In this Review, we discuss adrenergic and non-adrenergic mechanisms controlling lipolysis and thermogenesis and provide a comprehensive overview of pro- and anti-lipolytic mediators.
Topics: Adipose Tissue; Adrenergic Agents; Adrenergic Antagonists; Lipolysis; Thermogenesis
PubMed: 29514884
DOI: 10.1242/jeb.165381 -
The New England Journal of Medicine Dec 1998
Review
Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Angina Pectoris; Antihypertensive Agents; Carbazoles; Carvedilol; Heart Failure; Humans; Hypertension; Propanolamines
PubMed: 9845712
DOI: 10.1056/NEJM199812103392407 -
The New England Journal of Medicine Jan 1982
Clinical Trial
Topics: Adrenergic beta-Antagonists; Anxiety; Clinical Trials as Topic; Costs and Cost Analysis; Humans; Propranolol
PubMed: 6119611
DOI: 10.1056/NEJM198201213060319 -
Deutsche Medizinische Wochenschrift... Apr 1998
Review
Topics: Adrenergic alpha-Antagonists; Humans; Hypertension; Male; Prazosin; Prostatic Hyperplasia
PubMed: 9581161
DOI: 10.1055/s-0029-1233226