Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As previously reported by this laboratory, an endogenous factor capable of inhibiting the specific binding of the radiolabeled cannabinoid agonist [3H]CP-55940 to its receptor can be released from nerve terminals in response to an influx of Ca++ induced by an ionophore (Evans et al., 1992). In the present report, we provide evidence that the endogenous ligand for the cannabinoid receptor can be released in response to a depolarizing stimulus (75 mM K+) in the presence of extracellular Ca++. K(+)-evoked release was not observed in the absence of extra-cellular Ca++ and was reduced by the specific calcium channel blockers verapamil and omega-conotoxin. The efflux of cannabinoid receptor binding activity is greatest within 2 min of stimulation with the Ca++ ionophore A23187. Within this period of time, the cannabinoid receptor binding activity was enhanced by the presence of a cocktail of peptidase inhibitors. Examination of the contribution of individual inhibitors for enhancing high K(+)-released material revealed a selectivity for captopril and thiorphan. The specificity of the released factor for the cannabinoid receptor was corroborated by its ability to compete with the aminoalkylindole radioligand [3H]WIN-55212 for binding to this receptor. Fractions from a semi-purified sample of the effluent demonstrated binding to the cannabinoid receptor and behaved as agonists in that these fractions could inhibit adenylate cyclase activity in neuroblastoma membrane preparations.
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PMID:Endogenous cannabinoid receptor binding activity released from rat brain slices by depolarization. 813 40

The effects of cannabinoid receptor agonists on the non-adrenergic non-cholinergic (NANC) inhibitory responses to electrical field stimulation in guinea-pig trachea were assessed. R-(+)-[2,3-dihydro-5-methyl-3-[(morpholilinyl) methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2; 10(-5) M) significantly enhanced the frequency-dependent response to electrical stimulation. The same concentration of R-(N)-(2-hydroxy-1-methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (R(+)methanandamide) and 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) did not affect significantly the electrically induced inhibitory NANC responses. The effect of WIN 55,212-2 was not modified by the cannabinoid CB1 and CB2 receptor-selective antagonists, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 10(-5) M) and N-(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528; 10(-5) M), respectively. Moreover, the nitric oxide synthase inhibitor, L-NG-nitro-arginine methyl ester (L-NAME; 10(-4) M), but not the peptidase, alpha-chymotrypsin (2 U/ml), blocked the effect of WIN 55,212-2. Postsynaptically, WIN 55,212-2 did not produce any change of tracheal smooth muscle tone, either basal or histamine-induced, and did not interfere with the relaxant activity of the nitric oxide donor, sodium nitroprusside (10(-8)-10(-4) M). In conclusion, our results suggest that (a) cannabinoid CB1 and CB2 receptor stimulation does not alter the inhibitory NANC transmission in guinea-pig trachea, and (b) WIN 55,212-2 potentiates the NO-mediated component of the NANC relaxant response to electrical stimulation through a cannabinoid receptor-independent mechanism.
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PMID:Effects of cannabinoids on non-adrenergic non-cholinergic-mediated relaxation in guinea-pig trachea. 1295 67

The coexistence of type 2 diabetes and obesity presents a complex therapeutic challenge. Future combination tablets may include agents to address diabetes and any accompanying cardiovascular risk factors. Injectable agents that improve glycemic control and facilitate weight loss have recently become available: the soluble amylin analogue pramlintide provides an adjunct to insulin therapy in type 1 and type 2 diabetes, and the incretin mimetic exenatide can enhance prandial insulin release in type 2 diabetes. Orally active inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-IV, agonists of peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g ("dual PPARs"), and the CB1 cannabinoid receptor inhibitor rimonabant are advanced in clinical development. Many novel antidiabetic and antiobesity compounds are emerging in preclinical development.
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PMID:Drugs on the horizon for diabesity. 1618 70

The prevalence of obesity has been increasing dramatically in the last decades; the major metabolic complication of obesity is insulin resistance and type-2 diabetes because there are pathogenetic mechanisms linking obesity and type-2 diabetes. Diabetes is also rapidly increasing worldwide; such a description of the key stages in the evolution of type-2 diabetes may be of great interest for implementing antidiabetes treatment. In recent times, type-2 diabetes therapy has been based on drugs, which improve insulin sensibility or stimulate insulin secretion or slow down glucose absorption. Recently, an ADA and EASD consensus has been released to develop a common approach for the management of hyperglycaemia in adults. The development of new classes of blood-glucose-lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has increased the different possible options for the treatment of type-2 diabetes. Therapeutic approaches aiming to potentiate the biological effects of incretins include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-IV (DPP-IV) activity (incretin enhancers) will be very useful to slow down type-2 diabetes progression. Weight-loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favourable effects upon fat storage, nutrient metabolism and ultimately glucose tolerance or type-2 diabetes. When the therapeutic target is not achieved, insulin with metformin could be suggested, but is this approach the ideal one for all patients? Perhaps it is possible to delay the initiation of insulin therapy, therefore, the actual and future therapeutical options are considered in the present review.
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PMID:Time to insulin in type-2 diabetes: high hurdles or Santiago way? 1840 82

The goal of antidiabetes therapy is to reduce glycosylated hemoglobin (HbA(1c)) levels to prevent or minimize the microvascular complications associated with this disease, such as retinopathy, nephropathy, and neuropathy. Glycemic control, defined by the American Diabetes Association (ADA) as HbA(1c) <7.0%, is often difficult to achieve despite current treatments, including oral antidiabetes agents, such as biguanides (metformin), sulfonylureas, thiazolidinediones, dipeptidyl peptidase-IV (DPP-IV) inhibitors, meglitinides, and alpha-glucosidase inhibitors, as well as injectable agents, such as glucagon-like peptide-1 (GLP-1) analogues and insulin. In addition, antidiabetes treatments often become less effective over time as insulin resistance increases and pancreatic beta-cell function deteriorates. The latest ADA guidelines also recommend a range of interventions to control the multiple coexisting conditions associated with this chronic, progressive disease, including dyslipidemia and hypertension. This review highlights the new antidiabetes drug classes, which include incretin mimetics, cannabinoid receptor type 1 antagonists, and bile acid sequestrants, and compares these agents to established treatments with regard to efficacy and tolerability. The more recently developed antidiabetes drugs have been shown in clinical trials to produce glucose-lowering effects similar to those of established antidiabetes agents. Many of the new antidiabetes agents can be safely combined with established therapies to further improve glycemic control. In addition, the new agents may provide additional significant cardiometabolic benefits, including improving the lipid profile, lowering blood pressure, and reducing body weight. These new treatments may have the potential to greatly improve the management of type 2 diabetes.
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PMID:More choices than ever before: emerging therapies for type 2 diabetes. 1853 25

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety.In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.
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PMID:New drugs for type 2 diabetes mellitus: what is their place in therapy? 1884 4