Relations between structure and nicotine‐like activity: X‐ray crystal structure analysis of (−)−cytisine and (−)−lobeline hydrochloride and a comparison with (−)−nicotine and other nicotine‐like compounds

Abstract

1 Although (-)-cytisine is a rigid structure, it occurs in the crystal in two distinct but very similar conformations in which the pyridone ring is tilted relative to the charged nitrogen atom at much the same angle as the pyridine ring is in (-)nicotine hydrogen iodide. The carbonyl group in the pyridone ring of (--cytisine, however, is on the side of the ring opposite to the pyridine nitrogen in (-)-nicotine. 2 The pKa of (-)-lobeline HCI at 250C is 8.6 (approx), indicating that (-)-lobeline is at least 90% in the protonated form at physiological pH (7.6). It is probably the phenyl 2-keto-ethyl part of (-)-lobeline, rather than the phenyl 2-hydroxy-ethyl part, which interacts with the receptor. 3 The combination within one molecule of a charged ('onium') nitrogen atom lying out of the plane of, and some distance (4.5-6.5 A) from, an aromatic ring is common to many compounds with nicotine-like activity (e.g. nicotine, cytisine, choline phenyl ether bromide, dimethyl-phenyl-piperazinium (DMPP) iodide, coryneine iodide and m-hydroxyphenylpropyl trimethyl ammonium iodide). In some molecules the aromatic ring can be replaced by an unsaturated group, such as carbonyl (e.g. acetylcholine) or double-bonds (e.g. anatoxin). 4 Activity at nicotinic receptors appears to involve interactions between the positively charged nitrogen atom and a negatively charged group, probably close to cysteine residues 192 and 193 in the receptor. It is suggested that rather than specific groups in the molecule also being involved, activity at nicotinic receptors depends on interactions between a flat part of the drug containing double-bonds, or systems of double bonds, and a planar area in the receptor, possibly tyrosine or phenylalanine residues.

Up-Regulation of Brain Nicotinic Acetylcholine Receptors in the Rat during Long-Term Self-Administration of Nicotine: Disproportionate Increase of the α6 Subunit

“…The nAChRs not readily available for cytisine binding could be the more membrane-immersed or aggregated receptors, accumulating in animals self-administering nicotine because of channel desensitization or other factors. The structure of cytisine is rigid and more conformationally restricted than that of epibatidine (Barlow and Johnson, 1989;Wei et al, 2003). Consequently, cytisine may not access the binding sites of closely grouped or partially compartmentalized nAChRs.…”

Vesicular monoamine transporter 2: Role as a novel target for drug development

“…[100][101][102][103][104] Although lobeline has no structural resemblance to nicotine, and SARs do not suggest a common pharmacophore, 105 it has many nicotinelike effects, such as tachycardia and hypertension, 106 bradycardia and hypotension in anesthetized rats, 107 anxiolytic activity, 108 and improvement of learning and memory. 109 In contrast to nicotine, lobeline only marginally supports selfadministration in mice 110 and does not support self-administration in rats.…”

Experimental studies of charge density distribution in the crystals of cytisine and N-methylcytisine. Inside the Fake Tobacco

“…The standard resolution, room temperature crystal structures of cytisine (1) and N-methylcytisine (2) have been reported earlier [8,23,24]. Both alkaloids crystallize in noncentrosymmetric space group P 2 1 2 1 2 1.…”

“…It stimulates secretion of catecholamines, leading to increased blood pressure and sugar concentration, which alleviates nicotine withdrawal symptoms and stimulation of the respiratory system [2,7]. Comparison of the structures of nicotine and cytisine (Scheme 1) showed that the quasi-aromatic ring in cytisine and the pyridine ring in nicotine are associated in a similar way with respect to the nitrogen atom in the bispidine ring system (cytisine) and in the pyrrolidine ring (nicotine) [8]. Cytisine shows an affinity towards the specific subunits of nicotine acetylcholine receptors, nAChRs.…”