(-)-Lobeline hydrochloride

Lobeline hydrochloride, a nicotinic receptor agonist, acting as a potent antagonist at both α3β2 and α4β2 neuronal nicotinic receptor subtypes.

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.[Pubmed:2590771]

Br J Pharmacol. 1989 Nov;98(3):799-808.

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 pyridine nitrogen in (-)-nicotine. 2. The pKa of (-)-lobeline HCl at 25 degrees 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 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.

Effects of tension of the girth strap on respiratory system mechanics in horses at rest and during hyperpnea induced by administration of lobeline hydrochloride.[Pubmed:16111154]

Am J Vet Res. 2005 Jul;66(7):1167-74.

OBJECTIVE: To determine whether tension of the girth strap of a saddle would sufficiently affect rib motion and reduce lung volume to alter pulmonary resistance in horses. ANIMALS: 10 healthy adult horses. PROCEDURE: We used classical techniques to measure the effects of tightening a girth strap (15 kg of tension) on pulmonary dynamics during eupnea and hyperpnea in horses. Respiratory impedance was evaluated by use of oscillometry, and resistance and reactance data were partitioned into lung and chest wall components. Rib cage and abdominal contributions to tidal volume and minute ventilation were measured by use of respiratory inductance plethysmography. Effects of strap tension on functional residual capacity (FRC) were measured during eupnea by use of a helium-dilution technique. In a subgroup of 6 horses, we also measured transdiaphragmatic pressures during eupnea and hyperpnea induced by administration of lobeline hydrochloride (0.2 mg/kg, i.v.). RESULTS: Pulmonary resistance measured by use of oscillometry but not by use of classical methods was significantly increased by the tension of the girth strap. However, the increase in pulmonary resistance could not be explained by a decrease in FRC. Motion of the rib cage was significantly reduced during eupnea and hyperpnea. However, ventilatory variables (tidal volume, minute ventilation, and peak flows), FRC, and transdiaphragmatic pressures were unaltered by strap tension. CONCLUSIONS AND CLINICAL RELEVANCE: Although tension of the girth strap caused measurable changes in respiratory mechanics (loss of rib motion and increased pulmonary resistance), there was no evidence that ventilation was limited.

Ultrasound spirometry in the horse: a preliminary report on the method and the effects of xylazine and lobeline hydrochloride medication.[Pubmed:9451919]

Schweiz Arch Tierheilkd. 1997;139(12):558-63.

A new computerised ultrasound-based spirometry system according to Buess et al. (1995) modified by a double flow measurement facility was used to study pulmonary function in healthy horses and horses affected with subclinical and manifest chronic bronchiolitis (CB). The horses were first evaluated at rest without any medication. On another occasion all horses were tested following i.v. administration of xylazine (0.4 mg/kg) and following i.v. administration of lobeline hydrochloride (l.hy.; 0.2 mg/kg) to evaluate the effect of xylazine and l.hy. on different spirometric variables. Ultrasound-based spirometry proved to be an easily applicable method for lung function testing, even in difficult horses. However, there existed a pronounced physiological variation for all measured lung function parameters and no significant differences between healthy horses and horses with chronic bronchiolitis could be found except for the expiratory tidal volume (VTE p < 0.05). Individually, a marked decrease of variability from breath to breath following either xylazine and l.hy. administration could be observed for all parameters, except the flow-time-ratio (Tpef./ Texp.) and the flow-volume-ratio (Vpef./Vexp).

Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice.[Pubmed:19268674]

Physiol Behav. 2009 Jun 22;97(3-4):503-6.

Lobeline is a partial nicotinic agonist and is currently being investigated as a therapeutic drug for several addictive disorders particularly for smoking cessation. The present study evaluated the effects of repeated (continuous and recurring) administration of lobeline on alcohol consumption (10% alcohol vs. water) and alcohol preference using a 2-bottle choice test procedure. Male C57BL/6J mice were individually housed and acclimatized to 10% alcohol. Immediately following the last day of alcohol acclimatization and attainment of consistent drinking pattern, mice (n=5/group) received subcutaneous injections of lobeline (3, 5, or 10 mg/kg) or saline. Groups received either repeated-recurring (3 injections, given every other day) or repeated-continuous (daily injections for 5 days) subcutaneous injections of lobeline. Fluid consumption (alcohol and water) was recorded daily. Results showed that lobeline significantly reduced alcohol consumption and alcohol preference during the repeated (recurring and continuous) administration phases, while total fluid consumption remained unchanged. These results provide support that nicotinic receptor based drugs may be useful as potential treatments for alcoholism.

Pharmacology of lobeline, a nicotinic receptor ligand.[Pubmed:9223582]

J Pharmacol Exp Ther. 1997 Jul;282(1):410-9.

In this study we investigated the pharmacology of lobeline, a high affinity nicotinic ligand with a unique pharmacological profile, in different in vitro and in vivo tests. Although lobeline displaced [3H]-nicotine binding sites in the rat brain with a Ki of 4.4 nM, it did not activate alpha4beta2 expressed receptors in frog oocytes. The in vivo pharmacological effects of lobeline were highly complex. Lobeline, at the time of maximal effect, dose-dependently produced motor impairment and decreased locomotor activity and body temperature in mice after s.c. treatment. However, antinociception was present after intrathecal but not after s.c. administration of lobeline in the tail-flick tests. The behavioral effects of lobeline were not blocked by pretreatment with either mecamylamine or dihydro-beta-erythroidine. In addition, lobeline given s.c. enhanced nicotine-induced antinociception in a dose-related manner. No acute tolerance developed to either lobeline's behavioral or antinociceptive effect after s.c. or intrathecal administration, respectively. However, tolerance developed to lobeline's pharmacological effects after chronic treatment with the drug for 10 days (15 mg/kg, s.c. twice a day). Furthermore, cross-tolerance between lobeline and nicotine developed after chronic treatment with either drug. Although the alpha4beta2 receptor is unlikely to mediate the agonist effects of lobeline, our results indicate that lobeline does interact with the nicotinic receptor in a novel fashion.

Lobeline hydrochloride, a nicotinic receptor agonist, acting as a potent antagonist at both α3β2 and α4β2 neuronal nicotinic receptor subtypes.

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