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

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

Synthesis of isoxazole and isoxazoline derivatives of retinoids: effects on growth and differentiation of tumor cells

The authors studied the effects of several newly synthesized isoxazole and isoxazoline analogs of retinoids on induction of terminal differentiation and "in vitro" growth of tumor cell lines. Some of the tested compds. exhibit: (a) ability to induce adipogenic conversion of Ha-ras-1 transformed FH06T1-1 chinese hamster fibroblasts: (b) antiproliferative activity toward tumor cell lines, including the erythroleukemic K562 and FL cell lines and the FH06T1-1 cell line. This data could be of interest in identifying drugs of possible application in exptl. anticancer therapy

Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models.

Cannabinoid CB2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB2 agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB2 agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB2 compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB2 receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB2 receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB1-mediated central side effects

Design, synthesis and growth inhibition activity of bis-epoxyethyl derivatives of stallimycin modified on the amidino moiety

Derivs. I [R = H, X = NCN (3) or NOH (4); X = O, R = H (5) or Me (6)] of stallimycin (distamycin A) modified at the C-terminal amidine moiety and tethered to a bis-epoxyethyl moiety (as DNA alkylating unit) at the N-terminal position have been prepd. and tested for in vitro cytotoxic activity against two different leukemic cell lines, K562 and L1210. None of the compds. without epoxide was active. A comparison of the biol. activity related to the diepoxy compds. 3-6 with different non-basic amidine modified moieties, showed low activity for the carbamoyl and N-Me carbamoyl derivs. (compds. 5 and 6, resp.), moderate activity for the amidoxime analog 4, and good activity for the cyanamidine deriv. 3

Design, Synthesis and Biological Evaluation of Hybrid Molecules Containing Conjugated Styryl Ketone and alpha-Bromoacryloyl Moieties

There was a major interest in the last years in the design of anticancer agents containing the 1,5-diaryl-3-oxo- 1,4-pentadienyl system. The modification of this pharmacophore by the introduction of an additional Michael acceptor represents a strategy to obtain novel potential antiproliferative agents. In a continuing study of hybrid compounds containing the α-bromoacryloyl moiety as potential anticancer drugs, we synthesized two novel series of hybrids 3a-i and 4a-i, in which this moiety was linked to the 1,5-diaryl-1,4-pentadien-3-one system. Many of the conjugates prepared (3b, 3c and 3g) demonstrated pronounced antiproliferative activity against five cancer cell lines, being more active than the reference compound Melphalan. Compounds 3e and 4b were also examined for their effects on the cell cycle progression of K562 cells. The detection of a sub-G1 peak upon incubation with these compounds suggested that 3e and 4b also exert their growth inhibiting effects by induction of apoptosis

7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB2 Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists

Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo- [1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB2 receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20: hCB2 Ki = 2.5 nM, SI = 166; 21: hCB2 Ki = 0.81 nM, SI = 383; 38: hCB2 Ki = 15.8 nM, SI > 633; 56: hCB2 Ki = 8.12 nM, SI > 1231; (R)-58: hCB2 Ki = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated and it was found that the (R)-enantiomers exhibited greater affinity at the CB2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series behaved as agonists, exhibiting functional activity at the human CB2 receptor

Synthesis and Biological Evaluation of 2-Alkoxycarbonyl-3-Anilino Benzo[b]thiophenes and Thieno[2,3-b]Pyridines as New Potent Anticancer Agents

Two new series of inhibitors of tubulin polymerization based on the 2-alkoxycarbonyl-3-(3’,4’,5’-trimethoxyanilino)benzo[b]thiophene and thieno[2,3-b]pyridine molecular skeletons were synthesized and evaluated for antiproliferative activity on a panel of cancer cell lines, inhibition of tubulin polymerization, cell cycle effects and in vivo potency. Antiproliferative activity was strongly dependent on the position of the methyl group on the benzene portion of the benzo[b]thiophene nucleus, with the greatest activity observed when the methyl was located at the C-6 position. Also, in the smaller thieno[2,3-b]pyridine series, the introduction of the methyl group at the C-6 position resulted in improvement of antiproliferative activity to the nanomolar level. The most active compounds (4i and 4n) did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. Compound 4i significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice

Synthesis and Biological Evaluation of 2-Substituted-4-(3’,4’,5’-trimethoxyphenyl)-5-Aryl Thiazoles as Anticancer Agents

Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH3>Me>>N(CH3)2. The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC50 values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3b induced apoptosis through the activation of caspase-2, -3 and -8, but 3b did not cause mitochondrial depolarization

Design, Synthesis, and Pharmacological Properties of New Heteroarylpyridine/Heteroarylpyrimidine Derivatives as CB2 Cannabinoid Receptor Partial Agonists

Recent developments indicate that CB2 receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB2 receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB2 receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7 oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB2 receptor while showing only modest affinity for the centrally expressed CB1 cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists