n-methylepibatidine and epibatidine

Epibatidine is a potent but nonselective nAChR agonist. Its biological effects appear to be mediated largely by alpha4beta2 nAChRs. Surprisingly, only a limited number of epibatidine analogues have been synthesized and evaluated in in vitro assays. Even fewer analogues have received in vivo pharmacological evaluation. In this paper, SAR studies directed toward epibatidine analogues will be reviewed.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Molecular Structure; Nicotinic Agonists; Pyridines; Receptors, Nicotinic; Stereoisomerism; Structure-Activity Relationship

Epibatidine analogues 3- 5, possessing the pyridine ring fused to the 2,3 position of the 7-azabicyclo[2.2.1]heptane ring, and analogue 8a, possessing a benzene ring fused to the 5,6 position, were synthesized by procedures involving key steps of trapping 2,3-pyridyne, 3,4-pyridyne, and benzyne with tert-butyl 1 H-pyrrole-1-carboxylate. Two epibatidine analogues, 6 and 7, which have the 2'-chloropyridine ring bridged to the 7-azabicyclo[2.2.1]heptane ring via a methylene group, were synthesized, where the key step was an intramolecular reductive palladium-catalyzed Heck-type coupling. Even though the conformationally restricted epibatidine analogues, 3- 7, and the benzo analogue 8a possess nAChR pharmacophore features thought to be needed for alpha(4)beta(2) binding, they all showed low affinity for nAChRs relative to epibatidine. These studies provide new information concerning the pharmacophore for nAChRs and suggest that nitrogen lone-pair directionality and steric factors may be important. Interestingly, N-methylepibatidine, prepared as a standard compound for the study of bridged analogues 6 and 7, was a potent nAChR mixed agonist antagonist.

Topics: Analgesics; Animals; Body Temperature; Bridged Bicyclo Compounds, Heterocyclic; Mice; Nicotinic Agonists; Nicotinic Antagonists; Pain; Pain Measurement; Pyridines; Radioligand Assay; Rats; Receptors, Nicotinic; Structure-Activity Relationship

Three-dimensional quantitative structure-activity relationship methods, the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA), were applied using a training set of 45 ligands of the (alpha4)2(beta2)3 nicotinic acetylcholine receptor (nAChR). All compounds are related to (-)-epibatidine, (-)-cytisine, (+)-anatoxin-a, and (-)-ferruginine, and additionally, novel diazabicyclo[4.2.1]nonane- and quinuclidin-2-ene-based structures were included. Their biological data have been determined by utilizing the same experimental protocol. Statistically reliable models of good predictive power (CoMFA r2 = 0.928, q2 = 0.692, no. of components = 3; CoMSIA r2 = 0.899, q2 = 0.701, no. of components = 3) were achieved. The results obtained were graphically interpreted in terms of field contribution maps. Hence, physicochemical determinants of binding, such as steric and electrostatic and, for the first time, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties, were mapped back onto the molecular structures of a set of nAChR modulators. In particular, changes in the binding affinity of the modulators as a result of modifications in the aromatic ring systems could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. These results were used to guide the rational design of new nAChR ligands such as 48-52 and 54, which were subsequently synthesized for the first time and tested. Key steps of our synthetic approaches were successfully applied Stille and Suzuki cross-coupling reactions. Predictive r2 values of 0.614 and 0.660 for CoMFA and CoMSIA, respectively, obtained for 22 in part previously unknown ligands for the (alpha4)2(beta2)3 subtype, demonstrate the high quality of the 3D QSAR models.

Topics: Alkaloids; Animals; Azocines; Bacterial Toxins; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Cyanobacteria Toxins; Drug Design; In Vitro Techniques; Ligands; Marine Toxins; Microcystins; Models, Molecular; Prosencephalon; Protein Subunits; Pyridines; Quantitative Structure-Activity Relationship; Quinolizines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Stereoisomerism; Tropanes

The carbon-11-labelled nicotinic acetylcholine receptor (nAChR) agonist N-methylepibatidine was evaluated in vitro and in vivo as a possible positron emission tomography (PET)-tracer for nicotinic receptors in the central nervous system (CNS). The racemic mixture and both enantiomers of N-methylepibatidine were compared. Biodistribution and metabolites for blood and brain of [C-11]N-methylepibatidine were determined in mice. Whole body rat PET data were acquired for both stereoisomers. The regional distribution of the N-methyl-(-)-epibatidine in the brain was determined by a PET scan in a pig. Characteristic differences were found for the in vivo behavior of the stereoisomers of [C-11]N-methylepibatidine.

Topics: Animals; Brain; Bridged Bicyclo Compounds, Heterocyclic; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Female; Male; Mice; Mice, Inbred ICR; Nicotinic Agonists; Pyridines; Rats; Stereoisomerism; Tissue Distribution; Tomography, Emission-Computed; Toxicity Tests