Relative Actions of Quaternary Methyl Derivatives of Tyramine, Dopamine and Noradrenaline

I The guinea-pig isolated ileum has been used to estimate the ability of substituted phenylalkylonium salts (related to nicotine) to stimulate or block receptors in ganglia. The effects of hexamethonium were used to indicate which were the most specific ganglion stimulants; these were tested on the blood-pressure of pithed rats and for neuromuscular blocking activity on the rat diaphragm preparation. 2 m-Hydroxyphenylpropyltrimethylammonium and 3,4-dihydroxyphenethyltrimethylammonium (coryneine, 'quaternary dopamine') were the most active and specific ganglion stimulants but their usefulness in vivo may be limited by their neuromuscular blocking activity. The analogous tertiary compounds are being investigated. 3 The affinities of substances which were blocking agents at ganglionic receptors were measured on the isolated ileum with m-hydroxyphenylpropyltrimethylammonium as agonist. The affinities of selected compounds for postganglionic receptors were measured in experiments on the ileum in the presence of hexamethonium and with carbachol as agonist.Some of the compounds were tested for neuromuscular blocking activity on the rat diaphragm. 4 Phenylbutyldiethylamine had ganglion-blocking activity greater than pempidine and little postganglionic blocking or neuromuscular blocking activity. Its triethylammonium analogue had higher ganglion-blocking activity but had appreciable neuromuscular blocking activity. 5 The aromatic ring system is not essential either for activity or affinity and the effects of substituents are not related to their effects on electron distribution. Stimulant activity is enhanced only by hydroxyl or amino groups in suitable positions; it is not improved by the presence of rigid features (double or triple bonds or a cyclopropane ring) in the side chain. Affinity is slightly increased by chloro or bromo groups in suitable positions but the unsubstituted compounds are among those with the highest affinity. Substituents have similar effects on affinity for postganglionic receptors, though for these receptors the compounds mostly have only about one-tenth of their affinity for ganglionic receptors.

Section: Ganglion Stimulantssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

The Specificity of Some Agonists and Antagonists for Nicotine‐sensitive Receptors in Ganglia

Barlow¹,

Bowman²,

Ison³

et al. 1974

“…There are also pharmacological reasons for believing that the phenyl 2-hydroxyethyl part is not likely to be involved. A 2-hydroxy group greatly reduces nicotine-like activity: the trimethylammonium derivative of adrenaline has feeble nicotine-like activity compared with coryneine (the trimethylammonium derivative of dopamine: Cuthbert, 1964) and 2hydroxy phenethyl trimethyl ammonium bromide has negligible activity compared with phenethyl trimethylammonium bromide (Barlow & Gonzalez, 1986). In lobeline the hydroxyl group is actually 3 carbon atoms from the nitrogen but the groups are arranged less than 3 A apart.…”

Section: Discussionmentioning

confidence: 99%

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

Barlow¹,

Johnson

1989

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.

“…Each dose was given to 2 animals but all four doses were not necessarily given to the same two animals. The quaternary methyl derivative of dopamine is 3-12 times more effective than nicotine as a ganglionic stimulant in a number of tissue preparations (Cuthbert, 1964). In 8 experiments on 3 sheep, i.c.v.…”

Section: Resultsmentioning

confidence: 99%

Thermoregulatory Changes Induced by Cholinomimetic Substances Introduced Into the Cerebral Ventricles of Sheep

Johnson

1975

Thermoregulatory responses have been recorded from Welsh Mountain sheep exposed to warm, neutral or cold environments while injections of cholinomimetic drugs and/or their antagonists have been given into a lateral cerebral ventricle. Carbachol and physostigmine inhibited panting of animals at high ambient temperature (ta), caused vasoconstriction and initiated shivering at neutral ta, and accentuated shivering at low ta. Rectal temperature (tre) invariably increased. Oxotremorine had apparently identical effects. Nicotine and another ganglionic stimulant, the quaternary methyl derivative of dopamine, had no effects on thermoregulation. Atropine given 10 min before injections of carbachol, physostigmine or oxotremorine completely inhibited their hyperthermic effects, but pretreatment with the ganglion‐blocking drug, pempidine, caused no inhibition. The cholinergic synapses that respond to cholinomimetic drugs injected into the lateral cerebral ventricles of sheep are therefore muscarinic and not nicotinic. When atropine was given to sheep exposed to cold, no detectable reduction of shivering occurred and tre decreased only slightly, even with doses of atropine far greater than needed to inhibit shivering induced by physostigmine. This may be because shivering is controlled by neural pathways unaffected by drugs administered intracerebroventricularly or because the cholinergic synapses activated by physostigmine do not carry the input from cold sensors.