GR 79236

IC50: 3.1 nM (Ki)

GR 79236, N-[(1 S, trans)-2-hydroxycyclopentyl] adenosine, is an highly potent and selective adenosine A1 receptor agonist. Adenosine A1 receptor is ubiquitous throughout the entire body, and ofter has an inhibitory function on most of the tissues.

In vitro: GR79236 is a highly potent and selective A1 receptor agonist which is originally developed for the treatment of Type 2 diabetes mellitus, as a cardioprotective agent and also for peripheral arterial occlusive diseases. GR79236 inhibited catecholamine-induced lipolysis in adipocytes at low concentrations [1]

In vivo: GR79236 has a pronounced effect on NEFA and TG levels in both acute and chronic animal models, thus establishing the potential of this approach for the treatment of T2D [1]. GR79236 also can inhibit neurogenic vasodilation in anaesthetized rats, inhibit electrical stimulation of superior saggital sinusinduced trigeminovascular nociceptive transmission and CGRP release in anaesthetized cats and inhibit trigeminal nociception in humans [2].

Clinical trial: The analgesic efficacy of GR79236 was evaluated in the dental pain model (primarily inflammatory pain state). No evidence of efficacy of GR79236 was found compared with placebo [3].

References:
[1] Kiesman WF, Elzein E, Zablocki J.  A1 adenosine receptor antagonists, agonists, and allosteric enhancers. Handb Exp Pharmacol. 2009;(193):25-58.
[2] Arulmani U, Heiligers JP, Centurión D, Garrelds IM, Villalón CM, Saxena PR.  Lack of effect of the adenosine A1 receptor agonist, GR79236, on capsaicin-induced CGRP release in anaesthetized pigs. Cephalalgia. 2005 Nov;25(11):1082-90.
[3] Sneyd JR, Langton JA, Allan LG, Peacock JE, Rowbotham DJ.  Multicentre evaluation of the adenosine agonist GR79236X in patients with dental pain after third molar extraction. Br J Anaesth. 2007 May;98(5):672-6. Epub 2007 Apr 7.

Improvement of ketoacidosis in the diabetic rat after the administration of the oral antilipolytic agent GR 79236.[Pubmed:8033512]

Clin Sci (Lond). 1994 May;86(5):593-8.

1. We assessed the effect of a novel oral antilipolytic agent, N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR 79236), in experimental diabetic ketoacidosis. Ketotic rats were gavaged with GR 79236 (1 mg/kg) or water (vehicle) and their blood/plasma/serum biochemistry and haematological profile was determined. 2. We found that GR 79236 reduced the plasma non-esterified fatty acid concentration. This effect was associated with the correction of blood/plasma/serum biochemical variables (beta-hydroxybutyrate, acetoacetate, triacylglycerol) directly related to diabetic ketoacidosis, and of others (cholesterol, creatinine, creatine kinase and aspartate transaminase) which are not directly related to this metabolic abnormality. 3. There was, however, no evidence of GR 79236 lowering blood glucose in this model. One possible explanation for this observation is that GR 79236 stimulated gastric emptying leading to enhanced absorption of stomach contents when compared with untreated animals.

N-substituted adenosines as novel neuroprotective A(1) agonists with diminished hypotensive effects.[Pubmed:10479279]

J Med Chem. 1999 Sep 9;42(18):3463-77.

The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A(1) agonists with potent central nervous system effects and diminished influence on the cardiovascular system are reported and compared to selected reference adenosine agonists. The novel compounds featured are derived structurally from two key lead structures: 2-chloro-N-(1-phenoxy-2-propyl)adenosine (NNC 21-0041, 9) and 2-chloro-N-(1-piperidinyl)adenosine (NNC 90-1515, 4). The agonists are characterized in terms of their in vitro profiles, both binding and functional, and in vivo activity in relevant animal models. Neuroprotective properties assessed after postischemic dosing in a Mongolian gerbil severe temporary forebrain ischemia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an A(1) functional assay show similarities to some reference adenosine agonists. However, the new compounds we describe exhibit diminished cardiovascular effects in both anesthetized and awake rats when compared to reference A(1) agonists such as (R)-phenylisopropyladenosine (R-PIA, 5), N-cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR 79236, 26), N-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl]adenosine (Metrifudil, 28). In mouse permanent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine (NNC 21-0136, 12) exhibited significant neuroprotection at the remarkably low total intraperitoneal dose of 0.1 mg/kg, a dose at which no cardiovascular effects are observed in conscious rats. The novel agonists described inhibit 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED(50) values than for reference A(1) agonists. We conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1-piperidinyl]adenosine (NNC 21-0147, 13), representatives of a new series of P(1) ligands, reinforce the fact that novel selective adenosine A(1) agonists have potential in the treatment of cerebral ischemia in humans.

Cardiovascular and antilipolytic effects of the adenosine agonist GR79236.[Pubmed:8577816]

Pharmacology. 1995 Oct;51(4):224-36.

Adenosine is known to produce cardiovascular effects such as bradycardia and hypotension via activation of myocardial (A1) and vascular (A2) receptors and antilipolytic effects through activation of adipocyte (A1) receptors. We established the cardiovascular and antilipolytic profile of the adenosine A1 agonist GR79236 (N6-[(1S,trans)-2-hydroxycyclopentyl]-adenosine) and compared it with CPA (N6-cyclopentyl-adenosine). GR79236 was approximately 3-fold less potent than CPA in inhibiting in vitro lipolysis. In conscious rats, both agents were shown to have antilipolytic and glucose-lowering properties. In rats instrumented with telemetry transmitters, orally administered CPA was one log unit more potent than GR79236 as a hypotensive and bradycardiac agent. In summary, GR79236 is an A1-selective adenosine agonist which reduces heart rate and mean arterial pressure and produces decreased plasma lipids and glucose levels.

Functional characterization of three adenosine receptor types.[Pubmed:8358566]

Br J Pharmacol. 1993 Jul;109(3):693-8.

1. The purpose of the present study was to classify adenosine receptors into A1 and A2 subtypes in a wide range of isolated tissues and cell types (rat adipocytes and atria, guinea-pig ileum and atria (A1); guinea-pig aorta, dog coronary artery and human platelets and neutrophils (A2)) using the R- and S-diastereoisomers of N-phenylisopropyladenosine (PIA), N-cyclopentyladenosine (CPA), the novel compound, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236), N-[(2-methylphenyl)methyl]adenosine (metrifudil), 2-(phenylamino)adenosine (CV1808), and 2[[2-[4-(2-carboxyethyl)phenyl]ethyl]amino]-N- ethylcarboxamidoadenosine (CGS21680); N-ethylcarboxamidoadenosine (NECA) was used as a standard. 2. Results obtained in all tissue preparations previously reported to contain A1-receptors could be described by a single rank order of agonist potency: CPA > or = GR79236, R-PIA > or = NECA >> S-PAI > or = metrifudil > or = CV1808, CGS21680. 3. In contrast, two distinct rank orders of agonist potency were observed in preparations previously reported to contain A2-receptors. In dog coronary artery, human neutrophils and platelets the rank order of potency was: CV1808, CGS21680 > or = NECA > R-PIA > or = metrifudil > or = CPA > GR79236 S-PIA. However, in guinea-pig aorta the rank order was: NECA > metrifudil > R-PIA, CPA > CV1808, GR79236 > or = S-PIA, CGS21680. 4. The results of this study are consistent with the existence of three types of adenosine receptor: A1-and two subtypes of A2-receptor. The receptor present in dog coronary artery, human platelets and neutrophils, probably corresponds to the A2a subtype, whilst that present in the guinea-pig aorta may be of the A2b subtype.

GR79236 is a highly potent and selective adenosine A1 receptor agonist (Ki = 3.1 nM) that has analgesic and anti-inflammatory actions in humans and animals.

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