TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity

Abstract

Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and anxiety disorders. Based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214 (S-(+) enantiomer of mecamylamine), a noncompetitive NNR antagonist. TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety. TC-5214 was active in the forced swim test in rats (minimum effective dose (MED)=3 mg/kg i.p.), a classical depression model. It was also active in the behavioral despair test in mice (0.1-3.0 mg/kg i.p.), another model of depression. In the social interaction paradigm in rats, a model of generalized anxiety disorder (GAD), TC-5214 was active at a dose of 0.05 mg/kg s.c. In the light/dark chamber paradigm in rats, a model of GAD and phobia, TC-5214 was also active at a dose of 0.05 mg/kg s.c. Although TC-5214 shows modest selectivity among NNR subtypes, the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the alpha4beta2 NNRs. This is supported by the observation of similar effects with alpha4beta2-selective partial agonists such as cytisine and with alpha4beta2-selective antagonists such as TC-2216. TC-5214 was well tolerated in acute and chronic toxicity studies in mice, rats, and dogs, showed no mutagenicity and displayed safety pharmacology, pharmacokinetic and metabolic profiles appropriate for therapeutic development. Overall, the results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic effects and highlight the potential of NNR antagonists such as TC-5214 as therapeutics for the treatment of anxiety and depression.

Figure 1

Chemical structure of TC‐5214 (S‐(+)‐mecamylamine).

Figure 2

Effects of TC‐5214 in a forced swim test of depression in mice. TC‐5214 (0.1, 0.3, 1, and 3 mg/kg), saline, and fluoxetine (5 and 10 mg/kg) were administered intraperitoneally to male Swiss mice. Thirty minutes after dosing, mice were individually placed in a cylinder containing water (at a depth of 6 or 10 cm) from which they could not escape and the duration of immobility was measured. The results represent the mean ± standard error. *P < 0.05.

Figure 3

Effects of TC‐5214 in a forced swim test of depression in rats. Male Sprague–Dawley rats were individually placed in a cylinder containing water (at a depth of 13 or 35 cm) for 15 min on the first day, and were then put back in the water 24 h later for a 5‐min test. TC‐5214 (0.1, 0.3, 1, and 3 mg/kg), saline, and desipramine (10 mg/kg) were administered intraperitoneally. The duration of immobility during the 5‐min test was measured. The results represent the mean ± standard error. *P < 0.05.

Figure 4

Effects of TC‐5214 in a social interaction test of generalized anxiety in rats. Female Sprague–Dawley rats were initially placed individually in a test arena for a 5‐min familiarization trial. For the test trial on the next day, two animals were placed in the arena at the same time. The pairs were randomly allocated among the treatment groups receiving subcutaneous injections of saline, TC‐5214 (0.005, 0.05, or 0.17 mg/kg), or (−)‐nicotine (0.02 mg/kg). Social interaction behaviors and locomotor activity were compared between each group and the saline control group for 5 min. The results represent the mean ± standard error. *P < 0.05.

Figure 5

Effects of TC‐5214 in a light/dark test of generalized anxiety in rats. Sprague–Dawley rats were randomly allocated to treatment with a subcutaneous injection of saline, TC‐5214 (0.017, 0.05, or 0.17 mg/kg), or (−)‐nicotine (0.09 mg/kg). After treatment, each rat was returned to its home cage for 30 min, after which it was placed in the lit portion of the test arena facing the opening between a light compartment and a dark compartment. The percentage of time spent in the light compartment and locomotor activity were compared between each group and the saline control group. The results represent the mean ± standard error. *P < 0.05.