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| Clinical data | |
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| Other names | CNS5161 |
| Routes of administration | Intravenous,transdermal[1] |
| Drug class | NMDA receptor antagonist;Dissociative;Hallucinogen |
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| Pharmacokinetic data | |
| Eliminationhalf-life | 2.95 hours[2] |
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| Chemical and physical data | |
| Formula | C16H18ClN3S2 |
| Molar mass | 351.91 g·mol−1 |
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CNS-5161 is anNMDA receptor antagonist which was under development for the treatment ofneuropathic pain andcancer pain but was never marketed.[1][3][2] It is taken byintravenously ortransdermally.[1]
The drug is a highlypotent andselectivenoncompetitive antagonist of the NMDA receptor via theion channel ordizocilpine (MK-801)binding site, with anaffinity (Ki) of 1.8 nM.[2][4] It producesanalgesic,anticonvulsant, andneuroprotective effects in rodents.[2] There was also somedose-dependentmortality related torespiratory failure in rodents.[2]
In humans, the drug was found to produce milddissociative-like effects such asvisual disturbances andderealization at assessed doses of 250 to 2,000 μg intravenously inclinical trials.[2][4] In addition, it produced pronounced and dose-limitinghypertension.[2][4]
Thechemical synthesis of CNS-5161 andisotopologues has been described.[5][6]
CNS-5161 was under development by CeNeS Pharmaceuticals.[1][3] It reachedphase 2 trials prior to the discontinuation of its development.[1][3]
CNS 5161 is a novel NMDA ion-channel antagonist that interacts with the NMDA receptor/ ion channel site to produce a noncompetitive blockade of the actions of glutamate. Pre-clinical studies have demonstrated neuroprotective effects of CNS 5161 in the adult rat model of focal cerebral ischaemia, as well as anticonvulsant and analgesic effects. [...] The drug was well tolerated by recipients. Side-effects were dose-related, self limiting and comprised minor subjective sensory symptoms. [...] Minor symptoms fell into three general categories: nonspecific general effects, cardiovascular effects and sensory disturbance. [...] The sensory symptoms involved the peripheries and perioral area. They were universally mild, comprising dysaesthesia or numbness without any associated objective sensory deficit. All sensory symptoms resolved fully within 2 h. The nonspecific effects comprised sensations of lightheadedness, derealization, drowsiness, flushing and dizziness, not associated with any objective abnormal neurological or cardiovascular findings on examination. These all resolved fully within 1 h. [...] Certain pharmacodynamic effects were drug-related. It is likely that the minor sensory disturbances, drowsiness and flushing are also attributable to dosing. The aetiology of less specific complaints such as headache and dizziness is less clear, as they are frequently encountered in normal subjects who are required to fast and maintain bed rest for prolonged periods. The transient sensations of derealization experienced by some subjects were mild and self-limiting. They do not represent a significant psychoactive effect of CNS 5161 within the dose range studied.
Visual disturbances were experienced by 16.7% of patients receiving 250 μg and by 33.3% receiving 500 μg CNS 5161 HCl, but not during placebo treatment. An increase in blood pressure was observed in 8.3% of patients receiving 250 μg and in 50% of patients receiving 500 μg CNS 5161 HCl, compared with 15.4% during placebo treatment. The study was abandoned after two patients entered the 750 μg cohort due to a sustained systolic blood pressure response. [...] CNS 5161 HCl was reasonably well tolerated up to 500 μg. The most common adverse events were hypertension, headache and mild visual disorders. [...] CNS 5161 HCl (N-(2-chloro-5-(methylmercapto)phenyl)-N′-(3- (methylmercapto)phenyl)-N′-methylguanidine) (HCl) is a novel and selective noncompetitive NMDA antagonist with a Ki of 1.8 nM for the ion-channel binding site of the NMDA receptor complex [8]. [...] CNS 5161 appears to be different from traditional high-affinity NMDA antagonists since in preliminary preclinical and clinical studies no psychometric effects have been observed. In a previous study, CNS 5161 was well tolerated in human healthy volunteers, the major observation at high doses being a rise in blood pressure [9]. [...] The most common AEs reported by the patients in our study were mild headaches and visual disturbances. While the frequency of headaches was not different between CNS 5161 HCl and placebo treatment, visual disturbances occurred more often after CNS 5161 HCl compared with placebo. No other psychomimetic effects of CNS 5161 HCl were observed at any dosage in any patient. As previously shown with other noncompetitive NMDA antagonists [6, 16], CNS 5161, at dosages up to 500 μg, revealed less psychomimetic effects compared with ketamin and similar NMDA antagonists. [...] CNS 5161's psychotropic profile appears promising, which might lead to improved tolerability in the treatment of neuropathic pain syndromes compared with other NMDA receptor antagonists.
