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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
Author(s) -
Barlow R.B.,
Johnson O.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb14608.x
Subject(s) - cytisine , chemistry , nicotine , stereochemistry , acridine , ring (chemistry) , molecule , medicinal chemistry , nicotinic agonist , organic chemistry , receptor , biochemistry , neuroscience , biology
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 pK a of (−)−lobeline HCl at 25°C 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 Å) 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.