Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 3‘-Substituted Deschloroepibatidine Analogues. Novel Nicotinic Antagonists

Abstract

A series of 3'-substituted deschloroepibatidine analogues (3a-g and 4) showed high affinity for alpha4beta2 binding and relatively weak affinity for alpha7 nAChRs. The 3'-ethynyl (3g) and 3'-fluoro (3a) analogues with K(i) values of 0.02 and 0.037 nM, respectively, were the most potent. Even though the alpha4beta2 binding affinity of several of the analogues were equal to that of epibatidine, all of the compounds were weak agonists in the antinociceptive, hypothermia, and spontaneous activity test in mice. In contrast, all of the compounds were functional antagonists of nicotine-induced antinociception. In general, compounds 3a-g and 4 were more potent in the tail-flick assay than the hot-plate test. For example, the 3'-fluoro analogue 3a and the N-methyl-3'-iodo analogue 4 showed AD(50) values of 0.07 and 0.04 microg/kg, respectively, in the tail flick test and only 35 and 0% inhibition at 20 and 10 microg/kg in the hot-plate assay, respectively. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. The high affinity of the N-methyl-3'-iodo analogue 4 combined with its weak agonist and potent antagonist activity suggests that carbon-11 and iodine-123 analogues may be useful as PET and SPECT ligands, respectively, for studying nAChRs in vivo.

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

“…In fact, although small groups in position 2' are well tolerated, [74] substitution at position 3' (that is, 20) gives low efficacy agonists characterized by functional antagonistic properties in the tail-flick and hot-plate tests for analgesia. [75] Modifications on the basic nitrogen of 18 are not well tolerated: only N-methylation gives compounds with comparable affinity, whereas the N-ethyl analogue showed an affinity 500 times lower. [76] It is not surprising that compounds 21 showed much lower affinity than 18; however their K i values were still in the nanomolar range.…”

2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine Is a Novel Potent Competitive Antagonist of Human Neuronal α4β2 nAChRs

“…The challenge is to design analogs that are devoid of epibatidine's toxicity and low nAChR subtype selectivity. Efforts to modify epibatidine's structure include changes in stereochemistry, replacement of the N-H with other groups, changes in the 2-chloropyridine ring, replacement of the 2-chloropyridine ring with bioisosteric rings, changes in the 7-azabicyclo[2.2.1]heptane ring system, and conformationally constrained analogs (Carroll, 2004;Carroll et al, 2005;Huang et al, 2005;Wei et al, 2005).…”

A novel nicotinic acetylcholine receptor antagonist radioligand for PET studies

“…[15][16][17] Some of these analogues showed high affinity for nAChR; however, relative to epibatidine, they showed weak agonist activity in the mouse antinociception and body temperature tests. Importantly, all compounds were potent nAChR functional antagonists of nicotineÕs antinociceptive effects in the tail-flick procedure.…”

“…[ 11 C]NMI-EPB was obtained using a procedure similar to that described in our previous papers for the radiosynthesis of norepinephrine ligands 18,19 by alkylating 1.0 mg of the corresponding demethylated precursor 16 of NMI-EPB in DMF (0.25 mL) with [ 11 C]methyl iodide. After 5 min at 110°C, the product was purified by HPLC using a Phenomenex Luna C-18 semi-preparative column (250 mm · 10 mm, 5 lm) eluting with 20:80 CH 3 CN/0.2 M NH 4 OAc at a flow rate of 3.0 mL/min.…”