Photoswitchable Diazocine Derivative for Adenosine A Receptor Activation in Psoriasis.

Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A receptor (AR) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiation in an animal model of psoriasis. This was achieved by covalently bonding an adenosine-5'-methyluronamide moiety to a diazocine photochrome, whose singular photoswitching properties facilitated repeated interconversion between a thermally stable, biologically inactive agonist form and a photoinduced, pharmacologically active configuration.

Potent and Selective Human 5-HT Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity.

Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative (MRS8209; , 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HTR, compared to antitarget 5-HTR, and predicted to form a stable receptor complex using docking and molecular dynamics.

Structure of the human dopamine transporter and mechanisms of inhibition.

The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (β-CFT), the non-competitive inhibitor MRS7292 and Zn (ref.

2-Substituted (N)-Methanocarba A Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization.

2-Arylethynyl (N)-methanocarba adenosine 5'-methylamides are selective A adenosine receptor (AR) agonists containing a preestablished receptor-preferred pseudoribose conformation. Here, we compare analogues having bulky 2-substitution, either containing or lacking an ethynyl spacer between adenine and a cyclic group. 2-Aryl compounds -, , , , , , , , , and , lacking a spacer, had human (h) AAR values of 2-30 nM, and others displayed lower affinity.

Genetic and functional modulation by agonist MRS5698 and allosteric enhancer LUF6000 at the native A adenosine receptor in HL-60 cells.

The A adenosine receptor (AR) is an important inflammatory and immunological target. However, the underlying mechanisms are not fully understood. Here, we report the gene regulation in HL-60 cells treated acutely with highly selective AAR agonist MRS5698, positive allosteric modulator (PAM) LUF6000, or both.

2-Amino-5-arylethynyl-thiophen-3-yl-(phenyl)methanones as A Adenosine Receptor Positive Allosteric Modulators.

A adenosine receptor (AAR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure-activity relationship of 5-arylethynyl aminothiophenes as AAR positive allosteric modulators (PAMs). The derivatives were compared in binding and functional assays at the human AAR, indicating that some fluoro-substituted analogues have enhanced PAM activity.

First Potent Macrocyclic A Adenosine Receptor Agonists Reveal G-Protein and β-Arrestin2 Signaling Preferences.

()-Methanocarba adenosine derivatives (A adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at and C2 positions with terminal alkenes for ring closure.

Structure activity relationships of 5-HT and 5-HT serotonin receptor antagonists: N, C2 and 5'-Modified (N)-methanocarba-adenosine derivatives.

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT serotonin receptors as antagonists, predominantly containing branched N-alkyl groups. N-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HTRs, while only N-dicyclohexyl-methyl derivative 35 showed weak 5-HTR affinity (K 3.6 μM).

Adenosine A Receptor (AAR) Agonist for the Treatment of Bleomycin-Induced Lung Fibrosis in Mice.

Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lacking an effective treatment.

Effects of Purinergic Receptor Deletion or Pharmacologic Modulation on Pulmonary Inflammation in Mice.

COVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which consequently compromises alveolar exchange of O and CO.

Interaction of A adenosine receptor ligands with the human multidrug transporter ABCG2.

Various adenosine receptor nucleoside-like ligands were found to modulate ATP hydrolysis by the multidrug transporter ABCG2. Both ribose-containing and rigidified (N)-methanocarba nucleosides (C2-, N- and 5'-modified), as well as adenines (C2-, N-, and deaza modified), were included. 57 compounds out of 63 tested either stimulated (50) or inhibited (7) basal ATPase activity.

Targeting the A adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice.

Cisplatin is used to combat solid tumors. However, patients treated with cisplatin often develop cognitive impairments, sensorimotor deficits, and peripheral neuropathy. There is no FDA-approved treatment for these neurotoxicities.

A adenosine receptor agonists containing dopamine moieties for enhanced interspecies affinity.

Following our study of 4'-truncated (N)-methanocarba-adenosine derivatives that displayed unusually high mouse (m) AAR affinity, we incorporated dopamine-related N substituents in the full agonist 5'-methylamide series. N-(2-(4-Hydroxy-3-methoxy-phenyl)ethyl) derivative MRS7618 11 displayed K (nM) 0.563 at hAAR (∼20,000-fold selective) and 1.

Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets.

Nucleoside derivatives are well represented as pharmaceuticals due to their druglike physicochemical properties, and some nucleoside drugs are designed to act on receptors. The purinergic signaling pathways for extracellular nucleosides and nucleotides, consisting of adenosine receptors, P2Y/P2X receptors for nucleotides, and enzymes such as adenosine (ribo)kinase, have been extensively studied. A general modification, a constrained, bicyclic ring system (bicyclo[3.

Optical control of adenosine A receptor function in psoriasis.

Psoriasis is a chronic and relapsing inflammatory skin disease lacking a cure that affects approximately 2% of the population. Defective keratinocyte proliferation and differentiation, and aberrant immune responses are major factors in its pathogenesis. Available treatments for moderate to severe psoriasis are directed to immune system causing systemic immunosuppression over time, and thus concomitant serious side effects (i.

Biological Evaluation of 5'-(-Ethylcarboxamido)adenosine Analogues as Grp94-Selective Inhibitors.

The heat shock protein 90 kDa (Hsp90) family of chaperones is highly sought-after for the treatment of cancer and neurodegenerative diseases. Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum localized isoform that is responsible for the maturation of proteins involved in cell adhesion and the immune response, including Toll-like receptors, immunoglobulins, and integrins. Consequently, Grp94 has been implicated in many different diseases including cancer metastasis, glaucoma, and viral infection.

Adenosine A3 agonists reverse neuropathic pain via T cell-mediated production of IL-10.

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown.

Nucleotide P2Y receptor agonists are in vitro and in vivo prodrugs of A/A adenosine receptor agonists: implications for roles of P2Y and A/A receptors in physiology and pathology.

Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y receptor (P2YR) agonists and antagonists.

Structure activity relationship of novel antiviral nucleosides against Enterovirus A71.

Various (North)-methanocarba adenosine derivatives, containing rigid bicyclo[3.1.0]hexane ribose substitution, were screened for activity against representative viruses, and inhibition was observed after treatment of Enterovirus A71 with a 2-chloro-N-1-cyclopropyl-2-methylpropan-1-yl derivative (17).

Design and in vivo activity of A adenosine receptor agonist prodrugs.

Prodrugs (MRS7422, MRS7476) of highly selective A adenosine receptor (AR) agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2' and 3' hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.

Chronic Morphine-Induced Changes in Signaling at the A Adenosine Receptor Contribute to Morphine-Induced Hyperalgesia, Tolerance, and Withdrawal.

Treating chronic pain by using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance, and withdrawal, which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a twofold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord.

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels.

Pharmacological tools for chronic visceral pain management are still limited and inadequate. A3 adenosine receptor (A3AR) agonists are effective in different models of persistent pain. Recently, their activity has been related to the block of N-type voltage-gated Ca2+ channels (Cav2.