Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Abstract

A1 adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N6-cycloalkylmethyl 4′-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N6-dicyclopropylmethyl, Ki 47.9 nM) as a moderately A1AR-selective full agonist. Two stereochemically defined N6-methynyl group substituents displayed narrow SAR; larger than cyclobutyl greatly reduced AR affinity, and larger or smaller than cyclopropyl reduced A1AR selectivity. Nucleoside docking to A1AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger “A” forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39) and carbon chains of glutamates (EL2), and smaller subpocket “B” between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A1AR agonists. Truncated nucleosides, an appealing preclinical approach, have more drug-like physicochemical properties than other A1AR agonists. Thus, we identified highly restricted regions for substitution around N6 suitable for an A1AR agonist with anticonvulsant activity.

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

“…To test further the antidepressant effect of A 1 R signaling, we intraperitoneally injected (i.p.) WT mice with the selective A 1 R agonist MRS5474 (Tosh et al, 2012). MRS5474 induced a rapid antidepressant effect in FST, performed 1 hr after the injection (Figure 2D).…”

“…Furthermore, we describe here an antidepressant effect of the selective A 1 R agonist MRS5474 (Tosh et al, 2012). MRS5474 has been recently developed as a potent selective A 1 R agonist that is active in the CNS upon peripheral administration without cardiovascular side effects.…”

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

“…Various sterically constrained adenine nucleoside derivatives (Supplemental Material; (Supplemental Table 1) (Table 1) have been synthesized and studied for their potent binding to the A 1 AR (compound 2) (Tosh et al, 2012b) or A 3 AR (compounds 1, 3-9, 14-19, 21-28, 31, and 32) (Tosh et al, 2012a(Tosh et al, , 2015a. Many of these A 3 AR agonists reduce chronic neuropathic pain in a phenotypic screen, and the AR binding affinities of the previously reported nucleosides are provided (Supplemental Material; (Supplemental Table 2).…”

Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

“…Notably, in an attempt to harness these mechanisms for synthesis of novel therapeutic agents, A1 adenosine receptor agonists have been synthesized and demonstrate potential for binding to brain tissue in vitro (Maillard et al, 1994) and in animal models of mood disorders. However, these compounds have only been assessed for potential anti-convulsive (Tosh et al, 2012) and ischemic protective effects (Von Lubitz et al, 1996) and have not yet been applied to animal models of mood and behavior. Given these findings, studies are being pursued using pharmacologic agents that work through the A1 receptor.…”