Beta Adrenoreceptor Research Articles

Relation of Trp64Arg polymorphism of beta 3 adrenoreceptor gene with metabolic syndrome and insulin resistance in obese women.

Trp64Arg variant in beta 3 adrenoreceptor has been reported to be associated with increased body weight and insulin resistance. These risk factors are the ones that make up the so-called metabolic syndrome. The aim of our study was to investigate the relationship between metabolic syndrome and Trp64Arg polymorphism in the beta3 adrenoreceptor gene in obese women. A population of 531 obese women was analyzed in cross-sectional survey. A bioimpedance, blood pressure, a serial assessment of nutritional intake with 3 days written food records and biochemical analysis were performed. Genotype of beta 3 adrenoreceptor gene polymorphism (Trp64Arg) was studied. Prevalence of metabolic syndrome (MS) with ATP III definition was 47.1% (250 patients) and 52.9% patients without MS (n = 281 patients). Prevalence of beta 3 genotypes was similar in patients with metabolic syndrome (87.6% wild genotype and 12.4% mutant genotype) and without metabolic syndrome (87.9% wild genotype and 12.1% mutant genotype). Insulin and HOMA levels were higher in patients with mutant genotype than wild type, in patients with and without metabolic syndrome. In mutant group of beta3 adrenoreceptor gene patients have higher insulin and HOMA levels than wild type group, without relation with metabolic syndrome.

Abstract B04: Synthetic lethal targeting of E-cadherin-deficient cancers

Abstract Germline mutation of the E-cadherin gene (CDH1) genetically defines the inherited cancer syndrome hereditary diffuse gastric cancer (HDGC). HDGC is characterized by highly penetrant diffuse gastric cancer (DGC) and an elevated rate of lobular breast cancer (LBC). Somatic CDH1 mutations also occur frequently in the sporadic forms of these cancers. We propose that the loss of E-cadherin, a tumor suppressor gene, creates vulnerabilities in the cancer cell that can be exploited with drugs (“synthetic lethal” interactions). We are particularly interested in identifying drugs that can be used for the chemoprevention of advanced disease in HDGC family members by targeting the multifocal precursor lesions that occur in stomach and breast tissue. In the stomach, these early lesions are mucosally-confined stage T1a signet ring cell carcinomas. Up to 400 independent foci have been identified in the stomachs of CDH1 mutation carriers; these foci are genetically homogenous and are likely to only require the 2nd CDH1 hit for their initiation. To identify the vulnerabilities created by E-cadherin loss, we have conducted a genome-wide siRNA knockdown screen, a 4000 compound known drug screen and a 114,000 compound library screen in isogenic MCF10a breast cell lines with and without E-cadherin expression. The functional screen has shown that GPCR signaling proteins are highly enriched amongst the candidate synthetic lethal proteins, as well as many protein classes associated cell signaling and cytoskeletal function. Drugs that show increased activity against the E-cadherin-deficient cells include the JAK inhibitor LY2784544, the c-SRC inhibitor saracatanib, the beta-2 adrenoreceptor (GPCR) agonist formoterol, several HDAC inhibitors and statins. Detail on synergistic combinations involving many of these drugs is provided in the abstract entitled “Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors”. To identify mechanisms associated with E-cadherin synthetic lethality, we used the cell viability data from the siRNA screen to examine the distributions of cell viabilities for the genes that make up the major KEGG signaling pathways. Using the Kolomogorov-Smirnof method to test for significance, we identified the PI3K-AKT survival pathway as being central to E-cadherin's synthetic lethal associations. These findings pave the way for the development of rationally designed drug combinations for the chemoprevention and treatment of E-cadherin-negative cancers. Citation Format: Parry J. Guilford, Augustine Chen, Bryony Telford, Andrew Single, Henry Beetham, Tanis Godwin. Synthetic lethal targeting of E-cadherin-deficient cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B04.

Expressions of urothelial functional proteins in idiopathic detrusor overactivity patients refractory to antimuscarinic therapy with different urodynamic characteristics.

This study investigated the expressions of PGP9.5, P2 X 3 , muscarinic receptor (M3) and beta-3 adrenoreceptor (AR) in idiopathic detrusor overactivity (IDO) patients refractory to antimuscarinic treatment, and analyzed the correlation between protein expressions and clinical symptoms of IDO bladders with different urodynamic characteristics. Specimens of 48 IDO and 10 control patients without lower urinary tract symptoms were included. The levels of these proteins from bladder mucosa were determined by Western blotting. The expression levels of β3-AR and M3 receptor were similar between IDO patients and controls. When IDO patients were divided into two subgroups, phasic DO and terminal DO, the results showed that β3-AR level in the patients with phasic DO was significantly higher than that of the controls and terminal DO (Both P < 0.05). PGP9.5 and P2 X 3 levels were also significantly increased in phasic DO subgroup than controls. P2 X 3 receptor was positively correlated with PGP9.5 and β3-AR, and negatively correlated with the first sensation of bladder filling and voided volume in phasic DO. Similar expression M3 receptor and increased P2 X 3 levels in phasic DO, compared with the controls, indicate that dysregulation of purinergic bladder signaling may contribute to the pathogenesis of phasic DO refractory to antimuscarinics. Elevated expression of β3-AR in phasic DO but not in terminal DO patients may explain the different urodynamic characteristics of DO between the two subgroups. Our findings suggest that β3-AR agonist or P2 X 3 antagonist might be a good treatment choice for patients with phasic DO refractory to antimuscarinic therapy.

The Relationship Between Glutathione S-Transferase-P1 and Beta-2 Adrenoreceptor Genotypes with Asthmatic Patients in the Turkish Population.

Individual differences in the activity of enzymes that metabolize xenobiotics can impact health and disease. Beta-2 adrenoreceptor (ADRB2) is a functional G-coupled protein expressed in the vascular endothelium of lungs, alveolar walls, and the ganglions of cholinergic nerves which induces bronchodilation in response to catecholamines. Glutathione S-Transferase-P1 (GSTP1) is a candidate pi class GST gene, which controls pi class glutathione S-transferase activity. In this study we determined the relationship between the ADRB2 Arg16Gly polymorphism and GSTP1 polymorphisms, involved in bronchodilator response and oxidative stress, respectively, with susceptibility to asthma. In this study, 129 asthmatic patients and 127 healthy control cases were recruited to determine ADRB2 and GSTP1 genotypes by allele-specific polymerase chain reaction and restriction fragment length polymorphism assays, respectively. The ADRB2 genotype frequencies of the patients and control cases were found to be 10.9% (Arg16Arg), 48.8% (Arg16Gly), and 40.3% (Gly16Gly) and 24.4% (Arg16Arg), 36.2% (Arg16Gly), and 39.4% (Gly16Gly), respectively. GSTP1 genotype frequencies of patients and control cases were found to be 55% (Ile105Ile), 43.4% (Ile105Val), and 1.6% (Val105Val) and 75.6% (Ile105Ile), 22% (Ile105Val), and 2.4% (Val105Val), respectively. In the case of the GSTP1 gene, we found statistically significant differences in the genotype frequency of Ile105Val and the allele frequency of Val105 in the asthmatic group compared with the controls. Moreover, we observed a relationship between allele frequencies and clinical phenotypes including atopia nocturnal dyspnea, and steroid dependency in the asthmatic patients. Our results suggest that the GSTP1 Ile105Val polymorphism may be linked to the severeness of airway dysfunction.

Beta Blocker Induced Notorious Psychiatric Combination: Psychosis, Depression, and Suicide

Background The literature review shows that the most common psychiatric manifestation of beta adrenoreceptor blockers is depression, fatigue, and erectile dysfunction [1]. There was one case reported in the 1970s about psychosis-induced by beta adrenoreceptor blocker. This case report is the only one of its kind reporting an association between psychosis and beta adrenoreceptor blockers uses [2]. The case we would like to report is unique in its kind because it can be considered to be the second in literature to convey the rare, but detrimental, side effect profile of beta adrenoreceptor blockers: psychosis. Furthermore, our case report is demonstrating evidence of psychosis co-existing with worsening depressive symptoms, and emerging suicidal thoughts. Another large cohort study was conducted in the 1990s that assessed the risk of suicide in 58, 529 users of B-adrenoceptor blockers, calcium channel blockers, and angiotensin converting enzyme inhibitors (ACEIs). One hundred and forty suicide cases were reported in this study, and it was significant in users of B-adrenoceptor blockers. This study and further literature concluded that b-adrenoreceptor blockers were associated with increased risk of suicide [3,4]. However, calcium channel blockers and ACEIs were not associated with increased suicide risk [3].

Influence of beta-adrenoblockers on structural-functional heart indices in patients with acute q-wave myocardial infarction

The problem of myocardium infraction (MI) remains actually. An early postinfraction period is characterized with intensive remodeling of the left ventricle (LV) and high risk of dangerous complications that is ten times more than the monthly number of complications during the next year. The aim of research was the study of an influence of beta-1 adrenoreceptors on the heart rhythm variability, ectopic heart activity, daily profile of arterial pressure, postinfraction remodeling in patients with an acute Q-myocardium infraction. Methods. There were examined 235 patients with Q-myocardium infraction. There was evaluated the risk of forming LV aneurism, dynamic indices of combined daily monitoring of arterial pressure and electrocardiogram, echocardiography under influence of the complex treatment using beta-1 adrenoreceptors blockers.Results. Under an influence of treatment there was established the growth of temporal indices of the heart rhythm variability (HRV), spectral indices that present the parasympathetic influence on the background of decrease of the spectral components of sympathetic origin and mean HR, decrease of ectopic heart activity, normalization of daily profile of arterial pressure, improvement of systolic and diastolic function of LV.Conclusions. The use of beta-1 adrenoreceptors in the complex treatment of patients with acute Q-MI decreases the risk of forming LV aneurism, favors an improvement of HRV indices, ectopic heart activity, daily profile of arterial pressure, intracardiac hemodynamics

Anticholinergics/antimuscarinic drugs in asthma.

Anticholinergic alkaloids have been used for thousands of years for the relief of bronchoconstriction and other respiratory symptoms, and their use in the treatment of chronic obstructive pulmonary disease is well established. Acetylcholine, acting through muscarinic receptor (M) receptor, modulates multiple physiologic functions pertinent to asthma including airway muscle tone, mucus gland secretion, and various parameters of inflammation and remodeling. In addition, activation of M receptors may inhibit beta2 adrenoreceptor. These observations offer the rationale for the use of M receptors antagonists in the treatment of asthma. Short-acting antimuscarinic agents may be effective alone or in combination with short-acting beta agonists for the relief of acute symptoms. Long-acting antimuscarinic agents have emerged as potentially useful in the long-term treatment of difficult-to-control asthma. This review will analyze the mechanisms of action and therapeutic role of antimuscarinic agents on asthma including current guidelines regarding antimuscarinic drugs, recent studies in asthma, special populations to consider, and possible predictors of response.

Current role of treatment in men with lower urinary tract symptoms combined with overactive bladder.

Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in older men. The storage subcategory of LUTS is synonymous with overactive bladder (OAB) syndrome, which is an empirical diagnosis. Traditionally, alpha-blockers are widely prescribed to manage the LUTS of BPH, although storage symptoms may persist in many men despite treatment. Therefore, because therapies that target the prostate often fail to alleviate storage symptoms, they may not be the appropriate therapy for OAB. In past years, most physicians appeared to give more weight in elderly men to voiding symptoms than to storage symptoms and to be more concerned with initial treatment with anticholinergics for males with storage symptoms. Considering the recent increase in data on the efficacy and safety of combination treatment with alpha receptor antagonists and antimuscarinic agents, the standard pharmacologic treatment of patients with LUTS combined with OAB should be an alpha receptor antagonist and an antimuscarinic agent. Beta-3 adrenoreceptor agonists may also potentially be useful for the treatment of male LUTS combined with OAB.

Preventive and therapeutic effects of a beta adrenoreceptor agonist, dobutamine, in carrageenan-induced inflammatory nociception in rats.

We hypothesized that locally administrated β-adrenoreceptor agonist can modulate the inflammatory nociceptive parameters in carrageenan (CG)-induced peripheral inflammatory pain. This study was therefore aimed to assess the preventive and therapeutic effects of a β-agonist, dobutamine, by investigating its pretreatment and posttreatment actions on the inflammation-induced hypersensitivities (thermal hyperalgesia, mechanical allodynia) to cutaneous stimulation, edema, and several biochemical oxidant and anti-oxidant parameters in a rat model of CG-induced hind paw inflammation. Effects of dobutamine were compared with those of esmolol, a β-adrenoreceptor antagonist. CG injection to healthy rats lowered the thermal latencies (from 10.1 ± 0.2 to 4.9 ± 0.1 s) and mechanical thresholds (from 32.9 ± 0.5 to 18.9 ± 1.3 g) and caused the hyperalgesia and allodynia. In CG-induced inflamed paws, while intraplantar esmolol treatment (1 mg) produced significant decreases in latencies (4.1 ± 0.1 s) and thresholds (15.2 ± 2.4 g), dobutamine (1 mg) increased the latencies (11.3 ± 0.5 s) and thresholds (26.3 ± 2.8 g). In contrast to esmolol, dobutamine increased the superoxide dismutase level and decreased the myeloperoxidase, malondialdehyde, and nitric oxide levels in CG-induced inflamed paws. The present results can reveal that β-adrenoreceptors may play a role in inflammatory nociceptive processes, and locally treated β-adrenoreceptor agonists such as dobutamine can be a preferable, appropriate choice for the management of inflammatory nociception due to their preventive and therapeutic effects on CG-induced peripheral inflammatory nociception.

Marketing analysis of the drugs used for the treatment of affected military men with brain injuries

During the research the comparative analysis of protocols of medical care for patients with brain injuries and information of scientific literature and evidence-based medicine has been conducted. It has demonstrated that for the treatment of affected military men with brain injury the following groups of drugs are used: antibacterial agents for systemic use, psychoanaleptics, blood substitutes and perfusion solutions, antiepileptics, vitamins, peripheral vasodilators, cardiac drugs, calcium channel blockers, analgesics, antihemorrhagic drugs, drugs for treating wounds and ulcers, diuretics, antithrombotic agents, antiparkinsonian drugs, psycholeptics, vasoprotectives, beta adrenoreceptor antagonists, etc. Marketing analysis of certain groups of drugs has been conducted according to the following criteria: legal (registration in Ukraine), economic (commercial: country, company), pharmaceutical (types of dosage forms, the composition of active substances, method of application), pharmacotherapeutic (ATC-classification). The analysis of the domestic pharmaceutical market has shown that drugs for treatment of head injuries comprise 1034 drugs manufactured in 39 countries. It has been found that the Ukrainian producers are able to provide the necessary level of rendering medical care in treatment of the traumatic brain injury, they produce 549 names of drugs, and it is almost 53% of the total range of medicines. The first place among the Ukrainian companies manufacturing drugs for treatment of the brain injury has “Darnitsa pharmaceutical company” JSC, the second one – “Yuriа-Farm” Ltd., the third place – Pharmaceutical company “Zdorovye” Ltd. Foreign producers supply 485 drugs (47%). The leaders are India, Germany and Slovenia, which take the first, second and third places in the import of drugs, respectively.

Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Reply to a letter to the authors

Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Reply to a letter to the authors

Beta Blockers for Acute Traumatic Brain Injury: A Systematic Review and Meta-analysis

Traumatic brain injury (TBI) is associated with a systemic hyperadrenergic state. Through activation of beta adrenoreceptors, catecholamines may induce hypermetabolism and increase both cardiac and cerebral oxygen demands. We conducted a systematic review to appraise the available evidence examining the safety and efficacy of beta blockers in patients with acute TBI. We systematically searched CENTRAL, MEDLINE, EMBASE and the reference lists of relevant articles from database inception until March 19, 2013. The outcomes assessed were in-hospital mortality, functional outcome and quality of life. Common adverse effects of beta blockers were examined including clinically significant hypotension, bradycardia, bronchospasm and congestive heart failure. Data on study outcomes and quality were abstracted in duplicate. The results were summarized descriptively and quantitatively. One randomized controlled trial was found with a high risk of bias. Eight retrospective cohort studies were found with a moderate risk of bias; however, only four of these studies were identified as unique after excluding overlapping cases. The cohort studies reported mortality outcomes; however, none of these included studies assessed functional outcomes or quality of life. Meta-analysis on the cohort studies (n = 4,782 patients) demonstrated that exposure to beta blockers after TBI was associated with a reduction in the adjusted odds of in-hospital mortality by 65 % (pooled adjusted odds ratio 0.35; 95 % CI 0.27-0.45). The current body of evidence is suggestive of a benefit of beta blockers following TBI. However, methodologically sound randomized controlled trials are indicated to confirm the efficacy of beta blockers in patients with TBI.

Beta-3 adrenoreceptor stimulation reduces pulmonary vascular resistance in experimental models of acute and chronic pulmonary hypertension in pigs

Beta-3 adrenoreceptor stimulation reduces pulmonary vascular resistance in experimental models of acute and chronic pulmonary hypertension in pigs

Genetic Variation in the Beta 3-Adrenoreceptor Gene (Trp64Arg Polymorphism) and Its Influence on Anthropometric Parameters and Insulin Resistance Under a High Monounsaturated versus a High Polyunsaturated Fat Hypocaloric Diet

Objective: The aim of our study was to investigate the role of Trp64Arg polymorphism of the beta 3-adrenergic receptor (beta 3-AR) gene on metabolic changes and weight loss secondary to a high monounsaturated fat versus a high polyunsaturated fat hypocaloric diet in obese subjects. Material and Methods: A population of 260 obese subjects was analyzed. In the basal visit, patients were randomly allocated for 3 months to either diet M (high monounsaturated fat hypocaloric diet) or diet P (high polyunsaturated fat hypocaloric diet). Results: There were no significant differences between the positive effects (on weight, body mass index, waist circumference, fat mass) in either genotype group with both diets. With diet P and in genotype Trp64Trp, glucose levels (-6.7 ± 12.1 vs. -1.2 ± 2.2 mg/dl; p < 0.05), total cholesterol (-11.2 ± 8.1 vs. -1.0 ± 7.1 mg/dl; p < 0.05), low-density lipoprotein (LDL) cholesterol (-9.7 ± 10.1 vs. -2.2 ± 8.1 mg/dl; p < 0.05), triglycerides (-11.7 ± 13.1 vs. +1.7 ± 10.3 mg/dl; p < 0.05), homeostasis model assessment for insulin resistance (HOMA-R; -0.7 ± 1.1 vs. -0.3 ± 2.1 units; p < 0.05) and insulin levels (-1.8 ± 4.6 vs. -1.0 ± 9.1 mIU/l; p < 0.05) decreased. Conclusion: The metabolic effect of weight reduction by the two hypocaloric diets is greatest in subjects with the normal homozygous beta 3-AR gene. Improvements in total cholesterol, LDL cholesterol, triglyceride, glucose, insulin and HOMA-R levels were better than in the heterozygous group.

Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. A letter to the authors

Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. A letter to the authors

Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock

Betablockade has been shown to have cardioprotective effects in patients under perioperative stress. Besides animal model of septic shock and a small cohort of septic patients, these benefits have not been studied in septic shock patients who require norepinephrine administration. After correction of preload, an esmolol bolus (0.2-0.5mg/kg) followed by continuous 24h infusion was administered in septic patients with sinus or supraventricular tachycardia (HR > 120/min). Exclusion criteria were severe LV systolic dysfunction, atrioventricular blockade and norepinephrine infusion at rates over 0.5mg/kg/min. Monitoring with echocardiography and pulmonary artery catheter before, at 2, 6, 12, 24h following the start and 6h after ceasing of the esmolol drip. Patients were maintained normovolemic throughout the study and adjustments of concomitant norepinephrine infusion rates were made as required. Ten septic patients (mean age 54.4 ± 18.7), APACHE II 21.5 ± 6.2, CRP 275 ± 78mg/l, procalcitonin 14.5 ± 10.1mg/l, were given esmolol drip of 212.5 ± 63.5mg/h at start to 272.5 ± 89.5mg/h at 24h. Heart rate decreased from mean 142 ± 11/min to 112 ± 9/min (p < 0.001) with parallel insignificant reduction of cardiac index (4.94 ± 0.76 to 4.35 ± 0.72l/min/m(2)). Stroke volume insignificantly increased from 67.1 ± 16.3ml to 72.9 ± 15.3ml. No parallel change of pulmonary artery wedge pressure was observed (15.9 ± 3.2 to 15.0 ± 2.4mmHg) as well as no significant changes of norepinephrine infusion (0.13 ± 0.17 to 0.17 ± 0.19mg/kg/min), DO(2), VO(2), OER or arterial lactate. Saving the heart 30beats/min did not demonstrate adverse impact on global haemodynamics in rates above 110/min. Using well titratable betablocker seems to be safe and cardioprotective in septic shock patients with high cardiac output.

Mirabegron - a selective β3-adrenoreceptor agonist for the treatment of overactive bladder.

Overactive bladder is a common condition that significantly impacts overall quality of life. Antimuscarinics are the current main pharmacological option for treatment; however, many patients fail to adhere to therapy due to troublesome side effects. Mirabegron is a new beta-3 adrenoreceptor agonist which causes detrusor smooth muscle relaxation and has been proposed to be effective for treating overactive bladder symptoms. Mirabegron has been shown to be superior to placebo for reducing the mean number of incontinence episodes per 24 hours and the mean number of micturitions per 24 hours. Side effects such as dry mouth were observed at similar or lower rates than those seen for placebo and antimuscarinics. Higher doses of mirabegron were associated with minor increases in pulse rate and mean blood pressure. Mirabegron offers a new alternative for treating overactive bladder in patients for which antimuscarinics are either not tolerated or not appropriate.

Inhibition of cardiac Kir2.1–2.3 channels by beta3 adrenoreceptor antagonist SR 59230A

Kir2.x channels form the molecular basis of cardiac IK1 current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists. We found the β3-adrenoceptor antagonist SR59230A to be an inhibitor of Kir2.x channels. Therefore, we characterized the effects of SR59230A on Kir2.x and other relevant cardiac potassium channels.Cloned channels were expressed in the Xenopus oocyte expression system and measured with the double-microelectrode voltage clamp technique.SR59230A inhibited homomeric Kir2.1 channels with an IC50 of 33μM. Homomeric Kir2.2 and Kir2.3 channels and Kir2.x heteromers were also inhibited by SR59230A with similar potency. In contrast, no relevant inhibitory effects of SR59230A were found in cardiac Kv1.5, Kv4.3 and KvLQT1/minK channels. In hERG channels, SR59230A only induced a weak inhibition at a high concentration.These findings establish SR59230A as a novel inhibitor of Kir2.1–2.3 channels with a favorable profile with respect to additional effects on other cardiac repolarizing potassium channels.

418 The Effect of beta-2 Adrenoreceptor Agonist Inhalation on Lungs Donated after Cardiac Death in a Canine Lung Transplantation Model

418 The Effect of beta-2 Adrenoreceptor Agonist Inhalation on Lungs Donated after Cardiac Death in a Canine Lung Transplantation Model

Do crystal structures obviate the need for theoretical models of GPCRs for structure-based virtual screening?

Recent highly expected structural characterizations of agonist-bound and antagonist-bound beta-2 adrenoreceptor (β2AR) by X-ray crystallography have been widely regarded as critical advances to enable more effective structure-based discovery of GPCRs ligands. It appears that this very important development may have undermined many previous efforts to develop 3D theoretical models of GPCRs. To address this question directly, we have compared several historical β2AR models versus the inactive state and nanobody-stabilized active state of β2AR crystal structures in terms of their structural similarity and effectiveness of use in virtual screening for β2AR specific agonists and antagonists. Theoretical models, incluing both homology and de novo types, were collected from five different groups who have published extensively in the field of GPCRs modeling. All models were built before X-ray structures became available. In general, β2AR theoretical models differ significantly from the crystal structure in terms of TMH definition and the global packing. Nevertheless, surprisingly, several models afforded hit rates resulting from virtual screening of large chemical library enriched by known β2AR ligands that exceeded those using X-ray structures. The hit rates were particularly higher for agonists. Furthemore, the screening performance of models is associated with local structural quality, such as the RMSDs for binding pocket residues and the ability to capture accurately, most if not all critical protein/ligand interactions. These results suggest that carefully built models of GPCRs could capture critical chemical and structural features of the binding pocket, and thus may be even more useful for practical structure-based drug discovery than X-ray structures.