Development Of Agonists Research Articles

New horizons for selective 5-HT2C receptor ligands in psychiatric/neurological disorders.

The serotonin (5-HT) 5-HT2C receptor is a key contributor to obesity, autism, psychiatric (eg, depression, schizophrenia), and neurological diseases (eg, Parkinson's disease). The diversity and regulation of the 5-HT2C receptor signaling pathways are complex and provocatively suggest the importance of this receptor in an array of functions and indications. Therapeutic opportunities for both agonist and antagonist compounds that engage this receptor continue to emerge. The most advanced 5-HT2C receptor agonist in development is lorcaserin, which has completed phase III clinical trials and has submitted an NDA for the treatment of obesity (Pauli and Abdelghany, 2010). In a 12-week obesity trial, approximately 30% of patients at 10 mg b.i.d. showed >5% weight loss with lorcaserin with minimal adverse events. Earlier in development is another 5-HT2C receptor agonist vabicaserin for the treatment of psychiatric indications. Vabicaserin is a highly selective 5-HT2C agonist (Dunlop et al, 2010) with a strong preclinical profile supporting multiple indications. Despite initial concerns regarding potential cardiovascular liabilities, selective 5-HT2C agonists are proving to be devoid of these concerning side effects (Pauli and Abdelghany, 2010). Many different genetically modified animals have been created to improve understanding of the 5-HT2C receptor. Much of the early work focused on the 5-HT2C receptor knockout mouse that showed a hyperphagic obesity phenotype. However, the 5-HT2C receptor is subject to RNA editing leading to different forms of the receptor that are more (unedited) or less (fully edited) sensitive to the functional effects of 5-HT2C agonists. Therefore, more recently, transgenic animals have been developed that lock the 5-HT2C receptor into a fully edited (VGV) or an unedited (INI) isoform. Interestingly, animals locked into the fully edited VGV form of the receptor show failure to thrive, neonatal muscular hypotonia, decreased somatic growth, and reduced fat mass despite hyperphagia, characteristics consistent with Prader–Willi syndrome (Kawahara et al, 2008; Morabito et al, 2010). The link between Prader–Willi syndrome and the 5-HT2C receptor has also been made through regulation of the splicing of the 5-HT2C receptor by HBII-52, a small nucleolar RNA that affects 5-HT2C receptor function (Kishore and Stam, 2006). Patients with Prader–Willi syndrome do not express HBII-52 that regulates alternative splicing of the 5-HT2C receptor by binding to a silencing element in exon Vb (Kishore and Stam, 2006). Moreover, these VGV mice have reduced G-protein-coupling efficiency and agonist binding but show enhanced behavioral sensitivity and serotonergic neurotransmission due to increased cell-surface expression of the 5-HT2C receptor (Kawahara et al, 2008; Olaghere da Silva et al, 2010). Interestingly, both the nonedited INI mice and the fully edited VGV mice show anxiety-like phenotypes with the INI mice showing a depressant-like phenotype and the VGV mice showing an antidepressant-like phenotype (Mombereau et al, 2010). Taken together, these transgenic models continue to show the complexity of the regulation of this receptor and the corresponding complexity of phenotypes. The multitude of ways that the 5-HT2C receptor is regulated through different signaling pathways, RNA editing, and changes in receptor expression coupled with its involvement in multiple psychiatric and neurological illness place this receptor as a critical player in the understanding of CNS disorders.

Intravenous MN-221, a Novel, Highly Selective Beta2-Adrenergic Receptor Agonist, Improves Lung Function in Stable Moderate to Severe Chronic Obstructive Pulmonary Disease Patients

PURPOSE: MN-221 is a novel, highly selective β2 agonist in development for the treatment of acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). MN-221 has a greater selectivity for the human β2 receptors than commonly used β2 agonists (i.e., albuterol, levalbuterol, terbutaline). MN-221 has been studied in both stable asthmatics and in acute exacerbations of asthma with results indicating increased effects on FEV1 and minimal effects of heart rate and blood pressure. A 1-hour infusion has produced a markedly greater improvement in FEV1 than the 2-hour regimen ion stable asthmatics.

Pharmacogenetic characterization of indacaterol, a novel β2‐adrenoceptor agonist

Indacaterol is a novel beta(2)-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human beta(2)-adrenoceptor and in human primary airway smooth muscle (ASM) cells. Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human beta(2)-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3',5'-cyclic-monophosphate production was used as an outcome measure. In both the low- and high-expression recombinant GEVT 'wild type' cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the beta(2)-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3',5'-cyclic-monophosphate in response to beta(2)-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol. These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of beta(2)-adrenoceptors.

Ghrelin receptor agonist (TZP‐101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis

TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Cross‐Species Differential Plasma Protein Binding of MBX‐102/JNJ39659100: A Novel PPAR‐γ Agonist

Drug binding to plasma proteins restricts their free and active concentrations, thereby affecting their pharmacokinetic properties. Species differences in plasma protein levels complicate the understanding of interspecies pharmacodynamic and toxicological effects. MBX-102 acid/JNJ39659100 is a novel PPAR-γ agonist in development for the treatment of type 2 diabetes. Studies were performed to evaluate plasma protein binding to MBX-102 acid and evaluate species differences in free drug levels. Equilibrium dialysis studies demonstrated that MBX-102 acid is highly bound (>98%) to human, rat and mouse albumin and that free MBX-102 acid levels are higher in rodent than in human plasma. Interspecies differences in free drug levels were further studied using PPAR-γ transactivation assays and a newly developed PPAR-γ corepressor displacement (biochemical) assay. PPAR-γ transactivation and corepressor displacement by MBX-102 acid was higher in rat and mouse serum than human serum. These results confirm the relevance of interspecies differences in free MBX-102 acid levels.

Indacaterol provides sustained 24 h bronchodilation on once‐daily dosing in asthma: a 7‐day dose‐ranging study

Indacaterol is a novel, once-daily beta(2)-agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Studies were required to determine optimal dose(s) for continuing investigation. A dose-ranging study was undertaken to evaluate efficacy and safety of indacaterol. A total of 436 patients with persistent asthma receiving inhaled corticosteroids were randomized to 7 days treatment with once-daily indacaterol 50, 100, 200, or 400 microg via multi-dose dry-powder inhaler (MDDPI; Certihaler), indacaterol 400 microg via single-dose dry-powder inhaler (SDDPI), or placebo. Serial 24-h spirometry was performed on days 1 and 7. Vital signs, laboratory evaluations, and adverse events were monitored. All doses of indacaterol increased the mean time-standardized area under the curve of forced expiratory volume in 1 s (FEV(1)) from 22 to 24 h postdose (P <or= 0.001 vs placebo) on days 1 and 7, with clinically relevant treatment-placebo differences of 240, 260, 350, 300, and 380 ml on day 1 and 230, 220, 320, 250, and 270 ml on day 7 for indacaterol 50, 100, 200, and 400 microg via MDDPI and 400 microg via SDDPI, respectively. All doses increased mean FEV(1) (P < 0.05 vs placebo) from 5 min to 24 h postdose on days 1 and 7. All doses were well tolerated. Most adverse events were mild-to-moderate in severity: most frequently reported were respiratory, thoracic, and mediastinal disorders. Once-daily dosing with indacaterol provided sustained 24-h bronchodilation in patients with moderate-to-severe asthma, with a satisfactory overall safety profile. Indacaterol 200 microg appears the optimum dose, offering the best efficacy/safety balance.

Inflammation in Diabetes Mellitus: Role of Peroxisome Proliferator-Activated Receptor–α and Peroxisome Proliferator-Activated Receptor–γ Agonists

Patients with type 2 diabetes mellitus and/or the metabolic syndrome have considerable cardiovascular risk. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and with antihypertensive and some antihyperglycemic agents reduces this risk, but residual macrovascular morbidity and mortality persist, even in patients assigned to intensive multifactorial intervention programs. Therapeutic strategies that target inflammation and lipid abnormalities not well addressed by statins may offer additional opportunities for improving the prognosis of these patients. Inflammation, a key mechanism of atherogenesis, appears to have particular relevance to diabetic vascular complications, as well as in the development of diabetes itself. Oxidative stress and hyperglycemia also figure among the pathogenic factors that promote cardiovascular complications in patients with the metabolic syndrome and/or diabetes and may augment the ongoing inflammation. Peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma, members of the nuclear receptor family, form ligand-activated transcription factors that regulate key important metabolic pathways. PPARs have become therapeutic targets through the use of the fibrate class of antidyslipidemic drugs (PPAR-alpha) and the insulin-sensitizing thiazolidinediones (PPAR-gamma). The activation of these PPARs may also suppress inflammation and atherosclerosis. Recent clinical trials (Fenofibrate Intervention and Event Lowering in Diabetes [FIELD], Prospective Pioglitazone Clinical Trial in Macrovascular Events [PROactive]) have considered the impact of these PPAR agonists on cardiovascular disease, with mixed effects that require careful analysis, especially given ongoing trials and additional PPAR agonists in development.

Effect of indacaterol, a novel long-acting 2-agonist, on isolated human bronchi

Indacaterol is a novel beta2-adrenoceptor agonist in development for the once-daily treatment of asthma and chronic obstructive pulmonary disease. The present study evaluated the relaxant effect of indacaterol on isolated human bronchi obtained from lungs of patients undergoing surgery for lung carcinoma. Potency (-logEC50), maximal relaxant effect (Emax) and onset of action were determined at resting tone. Duration of action was determined against cholinergic neural contraction induced by electrical field stimulation (EFS). At resting tone, -logEC50 and Emax values were 8.82+/-0.41 and 77+/-5% for indacaterol, 9.84+/-0.22 and 94+/-1% for formoterol, 8.36+/-0.16 and 74+/-4% for salmeterol, and 8.43+/-0.22 and 84+/-4% for salbutamol, respectively. In contrast to salmeterol, indacaterol did not antagonise the isoprenaline response. Indacaterol's onset of action (7.8+/-0.7 min) was not significantly different from that of formoterol (5.8+/-0.7 min) or salbutamol (11.0+/-4.0 min), but it was significantly faster than that of salmeterol (19.4+/-4.3 min). EFS-induced contractions were inhibited with -logIC50 values of 6.96+/-0.13 (indacaterol), 8.96+/-0.18 (formoterol), 7.18+/-0.34 (salmeterol) and 6.39+/-0.26 (salbutamol). Duration of action was >12 h for indacaterol and salmeterol, and 35.3+/-8.8 and 14.6+/-3.7 min for formoterol and salbutamol, respectively. In isolated human bronchi, indacaterol behaved as a long-acting beta2-adrenoceptor agonist with high intrinsic efficacy and fast onset of action.

Food Does Not Affect the Pharmacokinetics of Tesaglitazar, a Novel Dual Peroxisome Proliferator‐Activated Receptor α/γ Agonist

Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (C(max)). Mean C(max) was approximately 18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] mumol/L), and median time to C(max) was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of t(max) was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.

Adenosine A2A agonists in development for the treatment of inflammation

Extracellular adenosine binds specifically to a family of four G protein-coupled cell-surface adenosine receptors (ARs). As the activation of the A2AAR modulates the activity of multiple inflammatory cells including neutrophils, macrophages and T lymphocytes, the receptor is considered to be a promising pharmacological target for the treatment of inflammatory disorders. Although adenosine binds nonselectively to all four AR subtypes, A2AAR selective agonists have been developed and shown to inhibit multiple manifestations of inflammatory cell activation including superoxide anion generation, cytokine production and adhesion molecule expression. A2AAR agonists are also vasodilators, but the inhibition of inflammation occurs at low doses that produce few or no cardiovascular side effects. Therefore, the selective activation of the A2AAR by these compounds holds significant potential in the treatment of inflammation.

Alternatives to Levodopa in the Initial??Treatment of Early Parkinson???s Disease

Parkinson's disease (PD) is primarily a disease of elderly patients. This article reviews current knowledge and recent developments relating to drugs that can be used as alternatives to levodopa as initial treatment of PD. Synthetic orally acting dopamine agonists have found increasing favour as an option for early PD in relatively young patients. This strategy is based on evidence that this approach may delay the onset of motor fluctuations, at least during the first 5 years of treatment. Subcutaneous apomorphine infusions may attenuate motor fluctuations in late-stage disease, and transdermal rotigotine, a dopamine agonist in development, has also been shown to be efficacious. The greater proclivity for dopamine agonists to cause psychotoxicity has, however, limited their routine use in the elderly. Selective monoamine oxidase type B (MAO-B) inhibitors, used as monotherapy, delay the need for the introduction of levodopa by about 9 months. These agents appear to be less efficacious than dopamine agonists but are better tolerated. Concern has been expressed about the potential of the MAO-B inhibitor selegiline (deprenyl) to induce cardiovascular adverse effects (orthostatic hypotension), either directly or through its amphetamine catabolites. Rasagiline is a new MAO-B inhibitor that is not broken down to amphetamine derivatives and is indicated as both monotherapy in early PD and as adjunctive therapy in PD patients with motor fluctuations. Two older classes of agents have undergone a resurgence of interest in recent years. Amantadine, which enhances dopaminergic transmission and has antiglutamate activity, is occasionally used as monotherapy but has recently been widely used as an antidyskinetic agent in late-stage PD. Anticholinergic drugs, such as benztropine (benzatropine) and orphenadrine also provide control of symptoms when used as monotherapy, but their psychotoxic, cognitive and autonomic adverse events make them inappropriate for the treatment of the elderly. Effective therapy in PD should prevent disease progression and abolish motor and cognitive handicap. Currently, none of the existing drugs meets all these needs.

41-5 - Transdermal delivery of xanomeline, and M1/M4 agonist in development for the treatment of Alzheimer's disease

41-5 - Transdermal delivery of xanomeline, and M1/M4 agonist in development for the treatment of Alzheimer's disease

The clinical effectiveness of 311C90 in the acute treatment of migraine.

Efficacy with currently marketed antimigraine compounds is less than optimal. 311C90 is a novel and selective 5-HT1D receptor agonist in development for the acute treatment of migraine. It shows evidence of both central and peripheral activity within the trigemino-vascular system and it is rapidly absorbed following oral administration. In clinical studies in migraine patients, a headache response at 2 hours has been observed in 65-81% of patients at doses above 1 mg. Favourable response rates are reported as early as 1 hour post-dose and efficacy rates continue to improve up to 4 hours. Headache recurrence is reported by 25-35% of patients and 311C90 is also effective in relieving the non-headache symptoms of migraine.