Potential therapeutic uses of mecamylamine and its stereoisomers

Nickell, Justin R.; Grinevich, Vladimir P.; Siripurapu, Kiran B.; Smith, Andrew M.; Dwoskin, Linda P.

doi:10.1016/j.pbb.2013.04.005

Cited by 45 publications

(32 citation statements)

References 231 publications

(256 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of rolipram, the high affinity binding sites mitigate the antidepressant effects of the drug [50]. Mecamylamine, a nicotinic parasympathetic ganglionic blocker that has been investigated for treating AUDs, also shows stereospecific binding which appears to be related to differing outcomes in behavioral assays [51]. …”

Section: Discussionmentioning

confidence: 99%

Intra-nucleus accumbens shell injections of R(+)- and S(−)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

Kasten

Boehm

2014

Behavioural Brain Research

View full text Add to dashboard Cite

The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh).The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2 hours, 3 hours into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (μg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug.

show abstract

Section: Discussionmentioning

confidence: 99%

Intra-nucleus accumbens shell injections of R(+)- and S(−)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

Kasten

Boehm

2014

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…Hypotension was considered an AE of special interest because dexmecamylamine is an isomer of the hypertension medication mecamylamine. However, the clinical dose of racemic mecamylamine used historically for the treatment of hypertension was considerably higher (mean daily dose >25 mg according to post-marketing data and approaching 100 mg/d in some patients) 7 than the dose of dexmecamylamine used in this study (1-4 mg BID). Adverse events potentially related to anticholinergic signs and symptoms were also assessed.…”

Section: Safety and Tolerability Assessmentsmentioning

confidence: 55%

“…9 This could be ascribed to dexmecamylamine having a different mechanism of action to approved antidepressants. 7 Nicotinic receptor compounds, such as the neuronal nicotinic receptor partial agonist ABT-089 (in clinical trials in patients with attention-deficit/hyperactivity disorder), have also been generally well tolerated, with a similar AE profile to that of dexmecamylamine. 10 Study completion rates were relatively high for a long-term trial (~40% at week 52), whereas discontinuation rates due to AEs (~10%) were low, indicating that the study was methodologically sound and that results were representative of the overall randomized patient population.…”

Section: Discussionmentioning

confidence: 99%

Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Tummala¹,

Desai²,

Szamosi³

et al. 2015

Journal of Clinical Psychopharmacology

View full text Add to dashboard Cite

Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.

show abstract

“…41 Some findings suggest that application of mecamylamine in some doses may lead to impairment of cognitive functions through disruption of anterior striatal BDNF signaling. 42,43 In this study, mecamylamine is also expected to reduce memory by using different methods such as reducing BDNF signaling, blocking nAchRs, decreasing the concentration of Ach and decreasing the plasticity of the neuron. Step-through latency ( The Impact of TSD and RSD on Memory Acquisition, Pain and Locomotor Activity SD affects different phases of memory formation.…”

Section: Investigating the Impact Of Nicotine And Mecamylamine On Behmentioning

confidence: 99%

Critical Role of CA1 Nicotinic Receptors on Memory Acquisition Deficit Under Induction of Total Sleep Deprivation and REM Sleep Deprivation

Javadmoosavi

Vaezi

nasehi

et al. 2018

Int Clin Neurosci J

View full text Add to dashboard Cite

Potential therapeutic uses of mecamylamine and its stereoisomers

Cited by 45 publications

References 231 publications

Intra-nucleus accumbens shell injections of R(+)- and S(−)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

Intra-nucleus accumbens shell injections of R(+)- and S(−)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Critical Role of CA1 Nicotinic Receptors on Memory Acquisition Deficit Under Induction of Total Sleep Deprivation and REM Sleep Deprivation

Contact Info

Product

Resources

About