RJR-2403

RJR-2403 Description:
Ki: RJR-2403 compound binds with high affinity to [3H]nicotine binding sites in rat brain (Ki 526 nM) but possesses weak affinity (36 mM) for the 125I-labeled a-bungarotoxin-sensitive nAChR subtype [1].
RJR-2403 (TC-2403, Rivanicline, (E)-metanicotine) is a drug which acts as a partial agonist at neural nicotinic acetylcholine receptors. It is subtype-selective, binding primarily to the α4β2 subtype. It has nootropic effects and was originally developed as a potential treatment for Alzheimer's disease, but a second action that was subsequently found was that it inhibits the production of Interleukin-8 and thus produces an antiinflammatory effect, and so it has also been developed as a potential treatment for ulcerative colitis. RJR-2403 also has stimulant and analgesic actions which are thought to be mediated through stimulation of noradrenaline release, and so it could potentially also have other applications.
In vitro: Prevous in vitro results suggest that RJR-2403 interacts with higher potency at CNS nAChR sub-types than at muscle, ganglionic or enteric nAChRs and has higher selectivity for CNS vs. muscle or ganglionic nAChRs than does nicotine. [2].
In vivo: The data from an in vivo study demonstrate the efficacy of oral RJR 2403 in improving cognitive performance and the long duration of action of RJR 2403 in young adult rats. In contrast, no significant memory improvement was seen in aged rats aged (24–26 months old) after RJR 2403 administration. The inability of RJR 2403 to enhanced cognitive functions in aged rats might be related to the decrease in the number of α4β2 nicotinic receptors, which occurs with age. A similar decreased responsiveness in aged rats has been seen with nicotine. The persistence of action of RJR 2403 provides additional promise for its potential as a treatment for cognitive dysfunction [3].
Clinical trial: Up to now, RJR-2403 is still in the preclinical development stage.
Reference:
[1] Damaj MI, Glassco W, Aceto MD, Martin BR.Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist. J Pharmacol Exp Ther. 1999;291(1):390-8.
[2] Bencherif M, Lovette ME, Fowler KW, Arrington S, Reeves L, Caldwell WS, Lippiello PM. RJR-2403: a nicotinic agonist with CNS selectivity I. In vitro characterization. J Pharmacol Exp Ther. 1996;279(3):1413-21.
[3] Edward D. Levin and N. Channelle Christopher. Persistence of nicotinic agonist RJR 2403-induced working memory improvement in rats. Drug Development Research. 55(2):97–103, 2002

Antiamnestic effect of alpha7-nicotinic receptor agonist RJR-2403 in middle-aged ovariectomized rats with Alzheimer type dementia.[Pubmed:17603674]

Bull Exp Biol Med. 2006 Dec;142(6):700-2.

The effects of chronic combined treatment with alpha7-nicotinic cholinergic receptor agonist RJR-2403 (1.0 mg/kg intraperitoneally) or alpha7-nicotinic cholinergic receptor antagonist mecamylamine (1.0 mg/kg intraperitoneally) and 17beta-estradiol (0.5 microg per rat intramuscularly) for 10 days on passive avoidance retention were studied in middle-aged (15 months) ovariectomized rats with experimental Alzheimer type dementia. Chronic treatment with RJR-2403 and 17beta-estradiol had a pronounced antiamnestic effect under conditions of Alzheimer type dementia in middle-aged ovariectomized rats.

[Co-administration of RJR-2403 with low dose of 17beta-estradiol on spatial learning in ovariectomized rats].[Pubmed:24340617]

Patol Fiziol Eksp Ter. 2013 Jul-Sep;(3):37-41.

The aim of this work was to study the influence of stimulation or blockade Nalpha7-cholinoreceptors on dynamics of spatial learning in water Morris maze and on behavior in the "open field" test in adult ovariectomized (OVX) females given with a low dose of 17beta-estradiol. Agonist of Nalpha7-cholinoreceptors - RJR-2403 (1.0 mg/kg, i.p.) or antagonist of Nalpha7-cholinoreceptors - mecamylamine (1.0 mg/kg, i.p.) treated chronically (14 days) alone and in a combination with low dose of 17beta-estradiol (0.5 micro/rat, s.c.) to OVX rats. Co-administration of RJR-2403 with low dose of 17beta-estradiol completely restored impaired spatial learning in water Morris maze in OVX females. Moreover, OVX rats treated with RJR-2403 and low dose of 17beta-estradiol demonstrated increased exploratory and grooming behavior in the "open field" test. Both mecamylamine alone and in combination with low dose of 17beta-estradiol failed to influence on spatial learning and failed to modify behavior in the "open field" test in OVX rats. The results of the present study suggest a positive effect of RJR-2403 in combination with low dose of 17beta-estradiol on spatial learning at estrogen deficiency.

[Chronic administration of RJR-2403 in combination with low-dose of 17beta-estradiol corrects passive avoidance learning in ovariectomized rats].[Pubmed:23901460]

Eksp Klin Farmakol. 2013;76(5):3-6.

The aim of this work was to study the effect of stimulation or blockade of Na7-cholinoreceptors with a low dose of 17beta-estradiol on the passive avoidance performance and behavior in the open-field test in adult ovariectomized (OVX) female rats. Agonist of Na7-cholinoreceptors RJR-2403 (1.0 mg/kg, i.p.) or antagonist of Na7-cholinoreceptors mecamylamine (1.0 mg/kg, i.p.) treated chronically (14 days) alone and in a combination with low dose of 17beta-estradiol (0.5 microg/rat, s.c.) to OVX rats. Co-administration of RJR-2403 with low dose of 17P-estradiol completely restored impaired passive avoidance performance in OVX females. OVX rats treated with RJR-2403 and low dose of 17beta-estradiol demonstrated increased exploratory and grooming behavior in the open-field test. Both mecamylamine alone and in combination with low dose of 17beta-estradiol failed to influence the passive avoidance learning and failed to modify behavior in the open-field test in OVX rats. The results of the present study suggest positive effect of RJR-2403 in combination with low dose of 17beta-estradiol on passive avoidance learning at estrogen deficiency.

The nicotinic agonist RJR-2403 compensates the impairment of eyeblink conditioning produced by the noncompetitive NMDA-receptor antagonist MK-801.[Pubmed:16644113]

Neurosci Lett. 2006 Jul 10;402(1-2):102-7.

The classical conditioning of eyelid responses using trace paradigms is a hippocampal-related model of associative learning, involving the activation of N-methyl-D-aspartate (NMDA) receptors. We have evaluated here the effects of NMDA-receptor blockage with the selective noncompetitive antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine, MK-801). Mice were implanted with stimulating electrodes on the supraorbitary nerve and with recording electrodes in the ipsilateral orbicularis oculi muscle. Animals were conditioned with a trace shock-SHOCK paradigm. MK-801-injected animals (0.02 mg/kg) seemed unable to acquire this type of associative learning task, but the latency and amplitude of their unconditioned eyelid responses was not affected by drug administration. The administration of the nicotinic agonist (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403; 2 mg/kg) was able to restore completely the acquisition of the conditioned response when administered both before and after MK-801. In vitro recordings of field excitatory postsynaptic potentials (fEPSPs) evoked in the hippocampal CA1 area by the electrical stimulation of the Schaffer collateral pathway indicates that RJR-2403 application to the bath enhance the release of glutamate by a presynaptic mechanism. These findings reveal that nicotinic acetylcholine receptors enhance glutamatergic transmission in hippocampal circuits involved in the acquisition of associative learning.

Rivanicline (RJR-2403; (E)-Metanicotine) is a neuronal nicotinic receptor agonist, showing high selectivity for the α4β2 subtype (Ki=26 nM); > 1,000 fold selectivity than α7 receptors(Ki= 36000 nM).

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