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Potential therapeutic uses of mecamylamine and its stereoisomers - PubMed

Review

Potential therapeutic uses of mecamylamine and its stereoisomers

Justin R Nickell et al. Pharmacol Biochem Behav. 2013 Jul.

Abstract

Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side effects at therapeutically relevant doses. As such, mecamylamine's use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(-)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder.

Published by Elsevier Inc.

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Figures

Fig. 1
Fig. 1

Chemical structures of racemic mecamylamine, S(+)-mecamylamine and R(−)-mecamylamine.

Fig. 2
Fig. 2. Mecamylamine inhibits nicotine-evoked [3H]DA overflow from superfused rat striatal slices in a concentration-dependent manner

Time course (top) of mecamylamine-induced inhibition of nicotine-evoked [3H]DA overflow. Arrow indicates time point at which nicotine was added to the superfusion buffer. Data are expressed as fractional release as a percentage of basal (mean ± SEM); n = 6 rats. Mean basal [3H]outflow was 0.75 ± 0.02 fractional release as percentage of tissue [3H] content. Time course data were used to generate [3H]DA overflow data (bottom). Control represents [3H]DA overflow in response to 10 μM nicotine (total [3H]DA overflow as a percentage of tissue [3H]-content, mean ± S.E.M.). Control response to nicotine in the absence of antagonist was 3.06 ± 0.24 [3H]DA overflow. Concentration-response curves were generated using nonlinear regression. Data are expressed as percentage of control; n = 5/group.

Fig. 3
Fig. 3. Schild analysis of mecamylamine inhibition of nicotine-evoked [3H]DA overflow from superfused rat striatal slices

After collection of the third sample, slices were superfused with buffer in the absence or presence of mecamylamine (1, 10, 100 μM) for 45 min before the addition of nicotine (0.1–100 μM) to the buffer, and superfusion continued for an additional 45 min. For each nicotine concentration, control response is that for nicotine in the absence of mecamylamine. Control represents [3H]DA overflow in response to nicotine alone (total [3H]DA overflow as a percentage of tissue [3H]-content, mean ± S.E.M.); n = 5 rats/mecamylamine concentration; control, n = 12 rats (mecamylamine was between-groups factor, control was contemporaneous with each mecamylamine concentration). Concentration-response curves were generated by nonlinear regression. Inset shows the Schild regression in which the log of dr–1 was plotted as a function of log of mecamylamine concentration, and data were fit by linear regression.

Fig. 4
Fig. 4. Saturation analysis of racemic [3H]mecamylamine binding to rat brain membranes in the absence (top) and presence of 1 mM S(−)nicotine (bottom)

Saturation analysis was determined using a concentration range of 20–1500 nM of racemic [3H]-mecamylamine in both the absence (top) and presence of nicotine (1 mM; bottom). Nonspecific binding was measured with 100 μM (±)-mecamylamine. Data are expressed as fmol/mg protein and represent the mean ± S.E.M. of three independent experiments. Curves were generated using nonlinear regression for a one-site model. The inset illustrates the Scatchard transformation of the specific binding data.

Fig. 5
Fig. 5. High concentrations of mecamylamine stereoisomers are required to compete for racemic [3H]-mecamylamine binding to rat brain membranes in the presence of 1 mM S(−)nicotine

Competitive binding assays were performed for racemic, S(+)- and R(−)-mecamylamine (1 nM - 1 mM) against 100 nM racemic [3H]-mecamylamine both in the absence (top) and presence of nicotine (1mM; bottom panel). Nonspecific binding was determined using 100 μM racemic mecamylamine. Data are expressed as fmol/mg protein and represent the mean ± SEM of three independent experiments. Curves were generated by nonlinear regression using a one-site model. Ki values are expressed as mean ± S.E.M. Ki values could not be calculated in the presence of nicotine.

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