Use of lobeline compounds in the treatment of central nervous sy

Details Use of lobeline compounds in the treatment of central nervous sy Use of lobeline compounds in the treatment of central nervous sy

1998-06-03

2000-07-11

Spivack, Phyllis G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514331, A61K 31445

Patent

active

060873760

ABSTRACT:
Lobeline and nicotine evoke [.sup.3 H]overflow from rat striatal slices preloaded with [.sup.3 H]dopamine ([.sup.3 H]DA). The lobeline-evoked overflow is calcium-independent and not antagonized by mecamylamine, suggesting a mechanism of action other than the stimulation of nicotinic receptors. Whereas nicotine stimulates nicotinic receptors, lobeline inhibits [.sup.3 H]DA uptake into synaptic vesicles and striatal synaptosomes. The results suggest that different mechanisms are responsible for the increase in striatal DA release evoked by lobeline and nicotine. [.sup.3 H]-Dihydrotetrabenazine [.sup.3 H]DTBZ), used routinely to probe a high-affinity binding site-on the vesicular monoamine transporter (VMAT2) binds to vesicle membranes from rat striatum. Lobeline inhibits [.sup.3 H]DTBZ binding with an IC.sub.50 of 0.90 .mu.M, consistent with its IC.sub.50 of 0.88 .mu.M for inhibition of [.sup.3 H]DA uptake into vesicles. These results suggest that the action of lobeline is similar to that of amphetamine and that it specifically interacts with DTBZ sites on VMAT2 to inhibit DA uptake into synaptic vesicles. d-amphetamine inhibits [.sup.3 H]DTBZ binding to vesicle membranes with an IC.sub.50 of 39.4 .mu.M, a concentration 20 times greater than reported for inhibition of VMAT2 function, suggesting that d-amphetamine interacts with a different site than lobeline on VMAT2 to inhibit monoamine uptake. These results suggest the use of lobeline and analogs thereof in treating individuals for diseases and pathologies of the central nervous system.

REFERENCES:
patent: 3901248 (1975-08-01), Lichtneckert et al.
patent: 4971079 (1990-11-01), Talapin et al.
patent: 5272144 (1993-12-01), Melloni et al.
patent: 5403595 (1995-04-01), Kitchell et al.
patent: 5414005 (1995-05-01), Schneider et al.
patent: 5468755 (1995-11-01), Cincotta et al.
patent: 5486362 (1996-01-01), Kitchell et al.
patent: 5536503 (1996-07-01), Kitchell et al.
patent: 5552429 (1996-09-01), Wong et al.
patent: 5576321 (1996-11-01), Krushinski, Jr. et al.
Levin, E.D., Drug Dev. Res., 38(3-4), 188-95 (abstract), 1996.
Barlow, R.B. et al., "Relationship 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," Br. J. Pharmacol., 98:799-808 (1989).
Brownstein, M.J. et al., "Neurotransmitter transporters," Rec. Prog. Hormone Res., 49:27-42 (1994).
Debler, E.A. et al., "Ascorbic acid and striatal transport of [.sup.3 H]1-methyl-4-phenylpyridine (MPP.sup.+) and [.sup.3 H]dopamine," Life Sci., 42:2553-2559 (1988).
Floor, E. et al., "Dynamic storage of dopamine in rat brain synaptic vesicles in vitro," J. Neurochem. 64, 689-699 (1995).
Liu Y. et al., "A molecular analysis of vesicular amine transporter," Behav. Brain Res. 73, 51-58 (1996).
Scherman, D., "Dihydrotetrabenazine binding and monoamine uptake in mouse brain regions," J. Neurochem. 47, 331-339 (1986).
Scherman, D. et al., "The regionalization of [.sup.3 H]dihydrotetrabenazine binding sites in the mouse brain and its relationship to the distribution of monoamines and their metabolites," Brain Res. 370, 176-181 (1986).
Scherman, D. et al., "[.sup.3 H]Dihydrotetrabenazine, a new in vitro monoaminergic probe for human brain," J. Neurochem. 50, 1131-1136 (1988).
Standaert, D.G. et al., "Treatment of central nervous system degenerative disorders," The Pharmacological Basis of Therapeutics, 9th ed. (Hardman J.G., Limberd L.E., Molinoff P.B., Ruddon R.W., and Gilman A.G., eds.), pp. 503-519, McGraw-Hill, New York (1996).
Olin, B.R. et al., "Smoking Deterrents," In Drug Facts and Comparisons. 1995 edition, ed. by B.R. Olin et al., pp. 3087-3095, St. Loius, MO: J.B. Lippincott Co., 1995.
Sloan, J.W. et al., "The comparative binding characteristics of nicotinic ligands and their pharmacology," Pharmacol. Biochem. Behav., 30:255-267 (1988).
Hamann, S.R. et al., "Hyperalgesic and analgesic actions of morphine, U50-488, naltrexone, and (-)lobeline in the rat brainstem," Pharmacol. Biochem. Behav., 47:197-201 (1994).
Brioni, J.D. et al., "Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test," Eur. J. Pharmacol., 238:1-8 (1993).
Decker, M.W. et al., "Effects of lobeline, a nicotinic receptor agonist, on learning and memory," Pharmacol. Biochem. Behav., 45:571-576 (1993).
Nunn-Thompson et al., "Pharmacotherapy for smoking cessation," Clin. Pharmacy., 8:710-720 (1989).
Prignot, J., "Pharmacological approach to smoking cessation," Eur. Respir. J., 2:550-560 (1989).
Kalyuzhnyy, V.V., "The treatment of nicotinism with the aid of lobeline and its influence on vegetative and vascular reactions," J. Neural. Psychiat., 68:1864-1870 (1968).
Stolerman, I.P. et al., "Dissociation between the locomotor stimulant and depressant effects of nicotinic agonists in rats," Psychopharmacol., 117:430-437 (1995).
Fudala, P.J. et al., "Further studies on nicotine-induced conditioned place preference in the rat," Pharmacol. Biochem. Behav., 25:1041-1049 (1986).
Geller, I. et al., "Effects of nicotine monomethiodide, lobeline, chlordiazepoxide, meprobamate and caffeine on a discrimination task in laboratory rats," Psychopharmacol. (Berl.), 20:355-365 (1971).
Schechter, M.D. et al., "Nicotine as a discriminative cue in rats: inability of related drugs to produce a nicotine-like cuing effect," Psychopharmacol. (Berl.), 27:379-387 (1972).
Reavill, C. et al., "Behavioral and pharmacokinetics studies on nicotine, cytosine and lobeline," Neuropharmacol., 29(7):619-624 (1990).
Romano, C. et al., "Sterespecific nicotine receptors on rat brain membranes," Science, 210:647-650 (1980).
Decker, M.W. et al., "Diversity of neuronal nicotinic acetylcholine receptors: lessons from behavior and implications for CNS therapeutics" Life Sci., 56:545-570 (1995).
Yamada, S. et al., "Brain nicotinic acetylcholine receptors biochemical characterization by neosurugatoxin," Mol. Pharmacol., 28:120-127 (1985).
Lippiello, P.M. et al., "The binding of L-[.sup.3 H]nicotine to a single class of high affinity sites in rat brain membrane," Mol. Pharmacol., 29:448-454 (1986).
S. Martin et al., "Opioid and nicotinic medellary hyperalgesic influences in the decerebrated rat," Pharmacol Biochem and Behav., 29 725-721 1988.
Broussolle, E.P. et al., "In vivo binding of .sup.3 H-nicotine in the mouse brain," Life Sci., 44:1123-1132 (1989).
Bhat, R.V. et al., "Regulation of brain nicotinic receptors by chronic agonist infusion," J. Neurochem., 56(6):1932-1939 (1991).
Sakurai, Y. et al., "Enhancement of [.sup.3 H]dopamine release and its [.sup.3 H]metabolites in rat striatum by nicotinic drugs," Brain Res., 242:99-106 (1982).
Takano, Y. et al., "Presynaptic modulation of the release of dopamine from striatal synaptosomes: difference in the effects of High K.sup.+ stimulation, methamphetamine and nicotinic drugs," Brain Res., 279:330-334 (1983).
Grady, S. et al., "Characterization of nicotine receptor-mediated .sup.3 H-dopamine release from synaptosomes prepared from mouse striatum," J. Neurochem., 59:848-856 (1992).

Affiliated with

Also associated with

Rating

Use of lobeline compounds in the treatment of central nervous sy does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Use of lobeline compounds in the treatment of central nervous sy, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of lobeline compounds in the treatment of central nervous sy will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-542758