Recent improvements in the development of A2B adenosine receptor agonists

Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis

Handbook of Cannabis and Related Pathologies

The two types of cannabinoid receptors named CB1 and CB2 are G protein coupled receptors. • Activation of the cannabinoid receptors causes inhibition of adenylate cyclase, and a subsequent decrease in the concentration of cyclic adenosine monophosphate in the cell, resulting in the inhibition of neurotransmission. • Δ9-Tetrahydrocannabinol (Δ9-THC), representing the psychoactive principle of Cannabis, was identified in 1964. • The CB1 receptor is expressed mainly in brain, lungs, liver, and kidneys; the CB2 receptor is expressed principally in the immune system. • Cannabinoid receptors are activated by phytocannabinoids (found in Cannabis), endocannabinoids (produced naturally in the body by humans and animals), and synthetic cannabinoids (produced chemically by humans)

New synthesis of diazepino[3,2,1-ij]quinoline and pyrido[1,2,3-de] quinoxalines via addition-elimination followed by cycloacylation

This paper describes a convenient and efficient synthesis of new fused tricyclic diazepino[3,2,1-ij] quinolines and substituted pyrido[1,2,3-de]quinoxalines. o-Phenylenediamines are transformed in the tricycle nucleus in only a few-step synthetic sequence to produce ethyl 2,8-dioxo-1,2,3,4-tetrahydro-8H [1,4]diazepino[3,2,1-ij]quinoline-7-carboxylate, ethyl 8-oxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij] quinoline-7-carboxylate and ethyl 2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate. The method is economical and simple to perform

A structural study of new potent and selective antagonists to the A(2B) adenosine receptor

Xanthines, including the natural derivatives theophylline and caffeine, are non-selective antagonists of adenosine. They are able to bind with good affinity to all four adenosine-receptor subtypes A(1), A(2A), A(2B) and A(3). In order to develop new drugs with few side effects, over the last few years many efforts have been devoted to the discovery of new adenosine antagonists with enhanced selectivity properties. The present paper reports the crystal structures of five new xanthinic derivatives, which display different affinities and selectivity properties towards the A(2B) receptor. Besides the crystallographic study, a structural comparison has been made with the calculated geometry of other xanthinic derivatives which are reported to have similar biological characteristics to understand the structural features controlling their affinity capabilities and selectivity. This structural comparison has been interpreted in the light of a recently published study on the binding of N-benzo[1,3]-dioxol-5-yl-2[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)1-methyl-1-H-pyrazol-3-iloxy]-acetamide to a model of the A(2B) receptor, which shows the most interesting affinity and selectivity properties

ChemInform Abstract: Adenosine Receptor Antagonists: Translating Medicinal Chemistry and Pharmacology into Clinical Utility

The first recorded report describing evidence for an AR originates from 1976. Now, 30 years later, advances in understanding the role of adenosine and its receptors in physiology and pathophysiology as well as new developments in medicinal chemistry of these receptors have enabled researchers to identify potential therapeutic areas for drug development. With the combination of pharmacological data, using selective ligands and genetically modified mice, important progress has been made toward an understanding of the role of ARs in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia-reperfusion injury, vascular injury, spinal cord injury, chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, inflammatory bowel disease, retinopathy, and Parkinson’s Disease (PD). Nonselective AR antagonists are used to maintain wakefulness (caffeine) and, less commonly at present, treat bronchospasm (theophylline, aminophylline, enprofylline). Currently a number of new selective AR agonists and antagonists are in testing for a variety of new indications. Therefore, the purpose of this review is to analyze the structure-activity relationships of the ligands synthesized as antagonists for the ARs. We have included some synthetic schemes in order to show the chemistry involved in this field. In particular, we will investigate antagonists under active development that selectively target the four known AR subtypes

Adenosine Receptor Antagonists: Translating Medicinal Chemistry and Pharmacology into Clinical Utility

The first recorded report describing evidence for an AR originates from 1976. Now, 30 years later, advances in understanding the role of adenosine and its receptors in physiology and pathophysiology as well as new developments in medicinal chemistry of these receptors have enabled researchers to identify potential therapeutic areas for drug development. With the combination of pharmacological data, using selective ligands and genetically modified mice, important progress has been made toward an understanding of the role of ARs in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia-reperfusion injury, vascular injury, spinal cord injury, chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, inflammatory bowel disease, retinopathy, and Parkinson’s Disease (PD). Nonselective AR antagonists are used to maintain wakefulness (caffeine) and, less commonly at present, treat bronchospasm (theophylline, aminophylline, enprofylline). Currently a number of new selective AR agonists and antagonists are in testing for a variety of new indications. Therefore, the purpose of this review is to analyze the structure-activity relationships of the ligands synthesized as antagonists for the ARs. We have included some synthetic schemes in order to show the chemistry involved in this field. In particular, we will investigate antagonists under active development that selectively target the four known AR subtypes

Preparation of fused purine derivatives as adenosine A3 receptor modulators.

Adenosine A3 receptor modulators of formulas I [R1, R2 = H, alkyl, aralkyl, aryl, etc.; R3 = aryl, alkyl, aralkyl; R4 = H, alkyl, aralkyl, aryl; X = CH, N] and II [R5, R6 = H, alkyl, aralkyl, aryl, etc.; R7 = alkyl, aryl, aralkyl; R8 = alkyl, aralkyl, aryl] are prepd. These compds. are useful as therapeutic agents for a no. of diseases and medical conditions that are mediated by the A3 receptor. The compds. of this invention are also useful as diagnostic agents for the A3 receptor. Thus, III was prepd., and had Ki value of 200 nM for binding to A3 receptors expressed in CHO cells

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2Receptor Agonists

Review on Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2 Receptor Agonist

Involvement of globus pallidus in the antiparkinsonian effects of adenosine A2A receptor antagonists.

An involvement of globus pallidus (GP) in the antiparkinsonian effects of A2A receptor antagonists has been proposed on the basis of the selective localization of A2A receptors on the striatopallidal pathway. In order to investigate this possibility, the present study evaluated rotational behavior in unilaterally 6-hydroxydopamine-lesioned rats following infusion of the water-sol. A2A receptor antagonist SCH BT2 into GP. SCH BT2 (5 g/1 l) altered neither motor behavior nor produced postural asymmetry by itself. However, when infused concomitantly with a parenteral subthreshold dose of L-DOPA (3 mg/kg i.p.) capable of inducing modest contralateral rotational behavior (34.7 20.7/1 h), SCH BT2 significantly potentiated the no. of contraversive rotations (167.4 16.3/1 h). These results suggest that A2A receptors located in the globus pallidus may be involved in the antiparkinsonian effects of A2A antagonists

Ligands for A(2B) adenosine receptor subtype

of adenosine receptors known as A1, A2A, A2B, and A3. The A2B subtype is a low affinity receptor, which couples to stimulation of adenylyl cyclase and also leads to a rise in intracellular calcium modulating important physiol. processes. Adenosine exhibiting activity at this subtype is at concns. greater than 10 M. The A2B receptors show a ubiquitous distributions, the highest levels are present in cecum, colon and bladder, followed by blood vessels, mast cells and lung. Through A2B receptors, adenosine also regulates the growth of smooth muscle cell populations in blood vessels, cell growth, intestinal function, inhibition of Tumor Necrosis Factor (TNF-), vascular tone, and inflammatory processes such as diarrhea and asthma. Potent and selective adenosine agonists are the result of modifications of the parent ligand adenosine by substitution, namely at N6 or C2 position of the purine heterocycle or at the 5' position of the ribose moiety. 5'-N-ethylcarboxamidoadenosina (NECA) is one of the most potent A2B adenosine receptor agonist. Classical antagonists for A2B adenosine receptors are xanthine analogs obtained from multiple substitutions of the parent heterocycle by C8 substitution combined with N1 and N3 (and sometimes N7) substitutions