RJR 2429 dihydrochloride

Synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands.[Pubmed:18363376]

J Org Chem. 2008 May 2;73(9):3497-507.

In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.

Characterization of functional nicotinic acetylcholine receptors involved in catecholamine release from the isolated rat adrenal gland.[Pubmed:12098588]

Eur J Pharmacol. 2002 Jun 20;446(1-3):83-7.

We tried to characterize nicotinic acetylcholine receptors involved in the release of catecholamines from the rat adrenal gland. The isolated adrenal gland was retrogradely perfused via the adrenal vein with Krebs-Ringer solution at a flow rate of 0.5 ml/min. Endogenous catecholamines, adrenaline and noradrenaline, released into the perfusate were electrochemically measured using high-performance liquid chromatography. (-)-Nicotine (3 x 10(-6)-3 x 10(-5) M) evoked the release of catecholamines (adrenaline >> noradrenaline) in a concentration-dependent manner. The (-)-nicotine (10(-5) M)-induced release of catecholamines was effectively attenuated by mecamylamine (10(-7) and 10(-6) M) (a relatively selective antagonist of alpha3beta4 nicotinic receptors), but not influenced by alpha-bungarotoxin (3 x 10(-7) M) (an antagonist of alpha7 nicotinic receptors) and dihydro-beta-erythroidine (10(-5) M) (a relatively selective antagonist of alpha4beta2 nicotinic receptors). (+/-)-Epibatidine (3 x 10(-7) and 10(-6) M) (a non-selective nicotinic receptor agonist), (-)-cytisine (10(-5) and 10(-4) M) (an agonist of beta4 nicotinic receptors) and (+/-)-2-(3-pyridinyl)-1-azabicyclo(2.2.2)octane (RJR-2429) (10(-5) M) (a putative agonist of alpha3beta4 nicotinic receptors) effectively evoked the release of catecholamines (adrenaline >> noradrenaline), while (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403) (up to 10(-4) M) (a selective agonist of alpha4beta2 nicotinic receptors) had no effect. The efficacies of these agonists are as follows: (+/-) epibatidine >> RJR-2429>(-)-cytisine>(-)-nicotine >> RJR-2403. These results suggest that alpha3beta4 nicotinic receptors are involved in the release of catecholamines from the rat adrenal gland.

The heterocyclic substituted pyridine derivative (+/-)-2-(-3-pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429): a selective ligand at nicotinic acetylcholine receptors.[Pubmed:9495846]

J Pharmacol Exp Ther. 1998 Mar;284(3):886-94.

The present report describes in vitro studies demonstrating that the heterocyclic substituted pyridine compound (+/-)-2-(3-pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429) is extremely potent in activating human muscle nicotine ACh receptor (nAChR) (EC50 = 59 +/- 17 nM; Emax = 110 +/- 09% vs. nicotine). RJR-2429 is markedly less potent in activating nAChRs in the clonal cell line PC12, with EC50 = 1100 +/- 230 nM and Emax = 85 +/- 20% when compared with nicotine. The activation of a putative alpha 3 beta 4-containing nAChR in PC12 by RJR-2429 reveals a potency intermediate between nicotine and epibatidine (EC50 of 20,000 nM for nicotine and 30 nM for epibatidine). Dose-response curves for agonist-induced ileum contraction indicate that RJR-2429 is equipotent with nicotine, having an EC30 of approximately 2 microM. RJR-2429 binds with high affinity to alpha 4 beta 2 receptor subtype (Ki = 1.0 +/- 0.3 nM), and chronic exposure results in significant up-regulation of the high-affinity [3H]nicotine binding sites. In addition, RJR-2429 does not activate nAChRs present in rat thalamic preparations but is a potent inhibitor of this receptor subtype. It antagonizes nicotine-stimulated ion flux in thalamic synaptosomes with an IC50 of 154 +/- 37 nM. It also is a potent partial agonist at nAChRs mediating dopamine release from rat synaptosomal preparations (EC50 = 2 +/- 1 nM; Emax = 40%; epibatidine and nicotine have EC50 values of 0.4 and 100 nM, respectively). A model for the structure-activity profile of RJR-2429, nicotine and epibatidine was derived by molecular forcefield and quantum mechanics calculations and may provide important clues for the development of ligands selective for nAChR subtypes as probes in the life sciences or as potential therapeutic tools.