CNS-5161

Last updated
CNS-5161
Clinical data
Other namesCNS5161
Routes of
administration 		Intravenous, transdermal [1]
Drug class NMDA receptor antagonist; Dissociative; Hallucinogen
ATC code
  • None
Pharmacokinetic data
Elimination half-life 2.95 hours [2]
Identifiers
  • 2-(2-chloro-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H18ClN3S2
Molar mass 351.91 g·mol−1
3D model (JSmol)
  • CN(C1=CC(=CC=C1)SC)C(=NC2=C(C=CC(=C2)SC)Cl)N
  • InChI=1S/C16H18ClN3S2/c1-20(11-5-4-6-12(9-11)21-2)16(18)19-15-10-13(22-3)7-8-14(15)17/h4-10H,1-3H3,(H2,18,19)
  • Key:JHVHEDNLONERHY-UHFFFAOYSA-N

CNS-5161 is an NMDA receptor antagonist which was under development for the treatment of neuropathic pain and cancer pain but was never marketed. [1] [3] [2] It is taken by intravenously or transdermally. [1]

Contents

The drug is a highly potent and selective noncompetitive antagonist of the NMDA receptor via the ion channel or dizocilpine (MK-801) binding site, with an affinity (Ki) of 1.8 nM. [2] [4] It produces analgesic, anticonvulsant, and neuroprotective effects in rodents. [2] There was also some dose-dependent mortality related to respiratory failure in rodents. [2]

In humans, the drug was found to produce mild dissociative-like effects such as visual disturbances and derealization at assessed doses of 250 to 2,000 μg intravenously in clinical trials. [2] [4] In addition, it produced pronounced and dose-limiting hypertension. [2] [4]

The chemical synthesis of CNS-5161 and isotopologues has been described. [5] [6]

CNS-5161 was under development by CeNeS Pharmaceuticals. [1] [3] It reached phase 2 trials prior to the discontinuation of its development. [1] [3]

See also

References

  1. 1 2 3 4 5 "CNS 5161". AdisInsight. 26 May 2010. Retrieved 30 January 2026.
  2. 1 2 3 4 5 6 7 Walters MR, Bradford AP, Fischer J, Lees KR (March 2002). "Early clinical experience with the novel NMDA receptor antagonist CNS 5161". Br J Clin Pharmacol. 53 (3): 305–311. doi:10.1046/j.0306-5251.2001.01541.x. PMC   1874317 . PMID   11874394. 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.
  3. 1 2 3 "Delving into the Latest Updates on CNS-5161 with Synapse". Synapse. 24 January 2026. Retrieved 30 January 2026.
  4. 1 2 3 Forst T, Smith T, Schütte K, Marcus P, Pfützner A (July 2007). "Dose escalating safety study of CNS 5161 HCl, a new neuronal glutamate receptor antagonist (NMDA) for the treatment of neuropathic pain". Br J Clin Pharmacol. 64 (1): 75–82. doi:10.1111/j.1365-2125.2007.02880.x. PMC   2000615 . PMID   17391323. 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.
  5. ↑ Gibbs, Andrew R.; Morimoto, Hiromi; VanBrocklin, Henry F.; Williams, Philip G.; Biegon, Anat (2002). "Synthesis of N -(2-chloro-5-methylthiophenyl)- N ′-(3-methyl-thiophenyl)- N ′-[ 3 H 3 ]methylguanidine, {[ 3 H 3 ]CNS‐5161}". Journal of Labelled Compounds and Radiopharmaceuticals. 45 (5): 395–400. doi:10.1002/jlcr.561. ISSN   0362-4803 . Retrieved 30 January 2026.
  6. ↑ Zhao, Yongjun; Robins, Edward; Turton, David; Brady, Frank; Luthra, Sajinder K.; Årstad, Erik (2006). "Synthesis and characterization of N -(2-chloro-5-methylthiophenyl)- N ′-(3-methylthiophenyl)- N ′-[ 11 C]methylguanidine [ 11 C]CNS 5161, a candidate PET tracer for functional imaging of NMDA receptors". Journal of Labelled Compounds and Radiopharmaceuticals. 49 (2): 163–170. doi:10.1002/jlcr.1033. ISSN   0362-4803 . Retrieved 30 January 2026.
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