1,721,001 research outputs found
Recent improvements in the development of A adenosine receptor agonists
Get PDFAdenosine is known to exert most of its physiol. 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 physiol. meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be assocd. 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 compds. can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N 6-, C2-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compds. 1-deoxy-1- 6-[N'-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl -N-ethyl--D-ribofuranuronamide (19, hA1 K i = 1050 nM, hA2A K i = 1550 nM, hA2B EC50 = 82 nM, hA3 K i > 5 M) and its 2-chloro analog 23 (hA1 K i = 3500 nM, hA2A K i = 4950 nM, hA2B EC50 = 210 nM, hA3 K i > 5 M) 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 M; hA2B EC50 = 3 nM) is currently under preclin.-phase investigation for treating coronary artery disorders and atherosclerosis
Preparation of isoquinolinyl cyclohexenylacrylamides as transient receptor potential vanilloid 1 (TRPV1) receptor antagonists
No full textTitle compds. [I; Y = Q1-Q3; R = H, Me; R1 = H, halo, OH, alkyl, alkenyl, alkoxy, alkylamino, (substituted) Ph, naphthyl, PhO, naphthyloxy, PhNH; n = 0, 1; X = (substituted) Ph, pyridyl, naphthyl, quinolyl, isoquinolyl; with specific exceptions], were prepd. Thus, (2E)-N-(isoquinolin-5-yl)-3-(2,6,6-trimethyl-3-phenoxycyclohex-1-enyl)acrylamide (3-step prepn. given) showed a Ki value of 4.93 nM in competition binding expts. with [3H]-RTX to TRPV1 expressed in rat spinal cord
Preparation of O-substituted-dibenzyl urea derivatives as TRPV1 receptor antagonists.
No full textTitle compds. [I; wherein X = halo, alkyl, alkoxy, (hetero)aryl; R1 = 2-hydroxyethyl, 2,3-dihydroxypropyl, etc.; R2 = CF3 or t-Bu; R3 and R4 independently = H, CN, alkyl, etc.; including all possible optical isomers and diastereoisomers thereof] were prepd. as TRPV1 (transient receptor potential vanilloid 1) receptor antagonists, useful in the treatment of, e.g., inflammation. Thus, the invention compd. II was prepd. and gave a Ki value of 60 nM in the radioligand binding assay
Preparation of N-aryl biarylcarboxamides as vanilloid-1 receptor modulators.
No full textThe title compds. I [A = CH or N; Z = (un)substituted Ph or pyridinyl], useful for the treatment of inflammatory diseases such as neuropathic pain, were prepd. and claimed. E.g., a multi-step synthesis of I [A = N; Z = 4-ClC6H4], starting from 6-chloronicotinoyl chloride and 4-chloroaniline, was given. Compds. I modulate the vanilloid TRPV1 receptor. For example, compd. I [A = N; Z = 4-ClC6H4] showed a Ki of 15 nM (13-17) in rat spinal cord and an IC50 of 0.83 nM (0.74-0.93) in cultured rat dorsal root ganglia neurons. Pharmaceutical compn. comprising the compd. I is disclosed
A synthetic approach for the preparation of rigid analogs of 1,3-dipropyl-7-methyl-8-aryl/heteroarylstyryl xanthines
No full textTethering the N-8-substituents of N-8-substituted styryl xanthine to N-7 has resulted in a series of conformationally constrained styryl xanthine analogs having the general formula 8. These new compounds have also been evaluated in order to investigate if the A2A adenosine receptor would be able to tolerate such a modification
Preparation of O-substituted-dibenzyl (thio)urea derivatives as TRPV1 receptor antagonists.
No full textTitle compds. [I; wherein A = (CH2)n, n is 0, 1, or 2; X = halo; Y = O or S; R1 = 2-hydroxyethyl, 2,3-dihydroxypropyl, etc.; R2 = CF3 or t-Bu] were prepd. as TRPV1 (transient receptor potential vanilloid 1) receptor antagonists, useful in the treatment of, e.g., inflammation. Thus, the invention compd. II was prepd. by substitution of 2-bromo-4-hydroxy-5-methoxy-N-acetyl benzylamine with 3-chloro-1,2-dihydroxypropane (84%) followed by deprotection in quant. yield and reaction with 4-trifluoromethylbenzyl isothiocyanate (58%) and gave a Ki value of 27 nM in the radioligand binding assay
O-SUBSTITUTED-DIBENZYL UREA-DERIVATIVES AS TRPV1 RECEPTOR ANTAGONISTS
No full textThe invention relates to compounds of formula (I) wherein R is halogen; R 1 is selected from 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2,2-dihydroxyethyl, 3,3-dihydroxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 3-amino-2-hydroxypropyl, ..
Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles
No full textThe reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines, e.g. I, and several com. available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus, e.g. II. The key intermediates employed proved to be suitable compds. by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings
Ligands for A(2B) adenosine receptor subtype
No full textof 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
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