RJR-2403: A CNS-Selective Nicotinic Agonist with Therapeutic Potential

Lippiello, Patrick M.; Bencherif, Merouane; Caldwell, William S.; Arrington, Sherry R.; Fowler, Kathy; Lovette, M.E.; Reeves, L.

doi:10.1007/978-1-4612-4116-4_41

Cited by 5 publications

(7 citation statements)

References 10 publications

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“…In contrast to this apparent limit on DHβE’s ability to block the effects of large doses of nicotine, this selective antagonist produced a complete antagonism of the discriminative stimulus effects of metanicotine and ispronicline in these nicotine-trained rats. This supports the suggestion (Lippiello et al ., 1996; Dunbar et al ., 2007) that these drugs are acting on the α4β2* receptor to produce their central effects.…”

Section: Discussionsupporting

confidence: 93%

“…As noted above, ispronicline has been evaluated in humans as a cognitive enhancer (e.g. Lippiello et al ., 1996; Lippiello et al ., 2006; Dunbar et al ., 2007). Metanicotine has been reported to be an analgesic in rodent pain models (Rowley et al ., 2008) and to have discriminative stimulus effects like those of nicotine in rats trained to discriminate 0.4 mg/kg nicotine base from saline (Damaj et al ., 1999).…”

Section: Introductionmentioning

confidence: 99%

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Nicotine-like discriminative and aversive effects of two α4β2-selective nicotine agonists, ispronicline and metanicotine

Winger¹

2021

Behavioural Pharmacology

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An attempt to determine the receptor selective nature of some of nicotine's behavioral effects was undertaken through the evaluation of the ability of two nicotinic α4β2*-selective receptor agonists to produce nicotine-like effects and modify rates of responding in a discrimination assay and in an aversive stimulus assay. A group of eight rats was trained to discriminate the presence of 1 mg/kg nicotine base. Another group of 4-6 rats was trained to report the aversive effects of nicotine by selecting a lever that produced one food pellet over a second lever that produced two food pellets and an intravenous injection of nicotine. Ispronicline and metanicotine, two α4β2*selective receptor agonists, increased selection of the nicotine-appropriate lever in a dose-related manner, up to a maximum of approximately 75%. The α4β2*-selective receptor antagonist, dihydro-beta-erythroidine blocked both the discriminative stimulus effects and the ratesuppressing effects of ispronicline, metanicotine, and small, but not large doses of nicotine. The nonselective antagonist, mecamylamine, antagonized the discriminative stimulus effects of each of the three nicotine agonists as well as the rate-decreasing effects of nicotine and metanicotine. Mecamylamine did not modify the ratedecreasing effects of ispronicline. Both ispronicline and metanicotine as well as nicotine were avoided in the drug + food vs. food choice situation. The receptor-selective nature of ispronicline and metanicotine was hereby confirmed in a behavioral assay, as were earlier reports that the discriminative stimulus effects of relatively small doses of nicotine are likely mediated by activity at the α4β2* nicotine receptor.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Nicotine-like discriminative and aversive effects of two α4β2-selective nicotine agonists, ispronicline and metanicotine

Winger¹

2021

Behavioural Pharmacology

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“…Since α-conotoxin MII failed to block in the vivo responses of TC-2559, the activity of the compound at α6β2* nAChRs also appeared to be negligible . In agreement with its in vitro selectivity profile, TC-2559 has been shown to potently increase the firing rate of DA cells in midbrain slices, and the performance of the compound in models of cognitive functions has been promising. , Furthermore, compared to nicotine, both TC-2403 and TC-2559 have exhibited significantly reduced degrees of side effects mediated by the ganglionic α3* and the muscle-type nAChRs, such as changes in blood pressure and heart rate and hypothermia. , Being one of the first truly α4β2-specific agonists, TC-2559 could be a valuable tool in future investigations of the physiological functions of α4β2* subtypes.…”

Section: Ligands For Neuronal Nachrsmentioning

confidence: 74%

Neuronal Nicotinic Acetylcholine Receptors: Structural Revelations, Target Identifications, and Therapeutic Inspirations

et al. 2005

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“…Ispronicline has been described as a partial agonist at the nicotinic α4β2* receptor (Dunbar et al ., 2006), and has been suggested for use as a cognitive enhancer in various clinical and nonclinical populations (e.g. Lippiello et al ., 1996; Dunbar and Kuchibhatla, 2006; Lippiello et al ., 2006; Dunbar et al ., 2007; Frölich et al ., 2011; Velligan et al ., 2012; Potter et al ., 2014; Buoli et al ., 2016), and as an analgesic (Gao et al ., 2010). Although metanicotine has not been approved for clinical use, it is acknowledged to have α4β2* selectivity (Bencherif et al ., 1996; Papke et al ., 2000) and has a profile of activity similar to that of ispronicline in animal models of memory (e.g.…”

Section: Methodsmentioning

confidence: 99%

Nicotinic aspects of the discriminative stimulus effects of arecoline

Winger

2021

Behavioural Pharmacology

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Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.0 mg/kg s.c.) was trained as a discriminative stimulus in a group of eight rats. The ability of various cholinergic agonists and antagonists to mimic or antagonize the discriminative stimulus effects of arecoline and to modify its rate-suppressing effects was evaluated. A muscarinic antagonist, but neither of two nicotinic antagonists, was able to modify the discriminative stimulus effects of arecoline, suggesting a predominant muscarinic basis of arecoline's discriminative stimulus effects in this assay. However, both nicotine itself and two nicotine agonists with selective affinity for the α4β2* receptor (ispronicline and metanicotine) produced full arecolinelike discriminative stimulus effects in these rats. The discriminative stimulus effects of the selective nicotine agonists were blocked by both the general nicotine antagonist mecamylamine and by the selective α4β2* antagonist, dihydro-beta-erythroidine (DHβE). Surprisingly, only DHβE antagonized the rate-suppressing effects of the selective nicotine agonists. These data indicate a selective α4β2* nicotine receptor component to the behavioral effects of arecoline. Although the nicotinic aspects of arecoline's behavior effects could suggest that abuse of arecoline-containing material (e.g. betel nut chewing) is mediated through nicotinic rather than muscarinic actions, further research, specifically on the reinforcing effects of arecoline, is necessary before this conclusion can be supported.

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RJR-2403: A CNS-Selective Nicotinic Agonist with Therapeutic Potential

Cited by 5 publications

References 10 publications

Nicotine-like discriminative and aversive effects of two α4β2-selective nicotine agonists, ispronicline and metanicotine

Nicotine-like discriminative and aversive effects of two α4β2-selective nicotine agonists, ispronicline and metanicotine

Neuronal Nicotinic Acetylcholine Receptors: Structural Revelations, Target Identifications, and Therapeutic Inspirations

Nicotinic aspects of the discriminative stimulus effects of arecoline

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