Epibatidine nAChR

A little over 10 years ago radiolabeled epibatidine (Houghtling et al. 1995) was introduced as a new ligand with extraordinarily high affinity for o4p2 nAChRs. Early reports suggested that [ H]-epibatidine binds to oc4p2-type receptors only, but this assertion was quickly questioned when it was noted that epibatidine binding exceeds... 

Fig. 3 Potential subunit compositions of nAChRs expressed in dopaminergic nerve terminals. A combination of ligand binding ([ H]-epibatidine and [ I]-a-conotoxin Mil), immunoprecipita-tion, and dopamine release data have led to the conclusion that rodent brain expresses a minimum of five different nAChR subtypes. Three of these (the two forms of a4p2 and a4aSP2) do not bind a-conotoxin Mil with high affinity (a-conotoxin Mll-resistant). The three a6-containing subtypes bind a-conotoxin Mil with high affinity (conotoxin Mil-sensitive). In general, the conotoxin-sensitive nAChR subtypes are activated by lower concentrations of agonist than are required to activate the a-conotoxin Mll-resistant subtypes (Salminen et al. 2007)...

Marubio et al., 1999 Williams et al., 1999). This speculation is corroborated by data suggesting that only neuronal nAChRs are important for the antinociceptive effects of epibatidine, while toxic effects might be mediated by peripheral nAChRs (Sullivan et al., 1994). 

Epibatidine s antinociceptive effect can be antagonized by pretreatment with the centrally active nAChR antagonist mecamylamine, but not with the peripheral antagonist hexamethonium, so the activation of central nAChRs is presumed to be essential for nicotinic analgesics (Sullivan et al., 1994). The high toxicity of epibatidine has been attributed to its lack of selectivity for specific neuronal nAChR subtypes and has precluded its development as a therapeutic agent. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

Sullivan, J. P., Briggs, C. A., Donnelly-Roberts, D., Brioni, J. D., Radek, R. J., McKenna, D. G., Campbell, J. E., Arneric, S. P., Decker, M. W. (+)-Epibatidine can differentially evoke responses mediated by putative subtypes of nicotinic acetylcholine receptors (nAChR) ligands in the rat tail-flick assay, Med. Chem. Res. 1994, 4, 502-516. 

Striatum, Flippocampus, Thalamus Relatively few studies have investigated the expression of AChRs outside the cortex in schizophrenia ( Table 4.2-7). However, studies done in the striatum, the hippocampus, and the thalamus have identified changes similar to those in the cortex including increased (striatum), unaltered (thalamus), or decreased (striatum, hippocampus) binding of [3H] nicotine to 4P2 type nAChRs in schizophrenia (Leonard et al., 1998 Court et al., 1999 Breese et al., 2000 Court et al., 2000). Supporting decreased expression of nicotinic type receptor in the striatum and the hippocampus, [3H]cytosine and [3H]epibatidine were similarly reported decreased in schizophrenia (Freedman et al., 1995 Breese et al., 2000 Durany et al., 2000). Additionally, a7 receptor binding in the hippocampus and the thalamus, as well as a.7 protein expression in the striatum, was reported to be decreased in this illness (Freedman et al., 1995 Leonard et al., 1998 Court et al., 1999). 

Pyridyl Ether Derivatives. A series of 3-pyridyloxymethyl heterocyclic ether compounds have been identified with subnanomolar affinity for brain nAChRs (336) (Table 14.10). Of particular note are A-85380 (81)and A-84543 (87). A-85380 exhibits high binding affinity (Ki = 52 pM), for nAChRs, comparable to that of epibatidine, the most potent nAChR ligand reported to date. This compound stimulated ion flux at the human nAChR subtypes at 163% relative to nicotine. 

N-Methylationof natural epibatidine (112) and its enantiomer (1 IS educed affinities for rat (X4J82 nAChRs by 6 and 2 times, respectively. With respect to functional assays, the impact of N-methylation on the activities of the two enantiomers is relatively small but differential, and theN-methyl products (124 and 125) showed modest enantioselectivities (358) (Table 14.12).N-Methyl ( )-epibatidine (114) demonstrated the analgesic activity in the mouse tail-flick model similar to that observed... 

The a4p2 nAChR is the predominant heteromeric receptor in the brain, binds nicotine and other nicotinic agonists, e.g. cytisine and epibatidine. As a principal nicotinic AChR is more ubiquitous and is predominant in cortex, striatum, superior colliculus, lateral geniculate nucleus and cerebellum. When activated it facilitates excitatory inputs and is present very early in the developing brain in various brain regions. 

Keywords Nicotinic acetylcholine receptor (nAChR) oic4p2 Nicotine Epibatidine Pyrrolizidine 2-azabicyclo[2.2.1 Jheptane Furo[2,3-h]pyridine Furo[3,2-b]pyridine Pharmacophore Pyridyl ether Furo[2,3-c]pyridine Furo[3,2-c]pyridine Molecular modelling... 

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