Chemistry:MK-212

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MK-212, also known as 6-chloro-2-(1-piperazinyl)pyrazine (CPP), is a serotonin receptor agonist of the arylpiperazine family.[1][2] It is specifically described as a non-selective serotonin 5-HT2 receptor agonist[3] or as a "relatively selective serotonin 5-HT2C receptor full agonist.[4] The drug promotes the secretion of serum prolactin and cortisol in humans.[5]

Use and effects

MK-212 did not produce hallucinogenic effects in humans at doses of up to 40 mg orally.[5] However, in other research, it occasionally produced LSD-like effects in alcoholic patients at a dose of 20 mg.[5] In addition, subsequent studies found that MK-212 at 20 mg significantly increased ratings of feeling high and feeling strange.[2][6][7]

Interactions

Pharmacology

Pharmacodynamics

MK-212 is an agonist of the serotonin 5-HT2 receptors, including the serotonin 5-HT2C, 5-HT2B, and 5-HT2A receptors, in that order of potency.[8][9][10] It is a full agonist of the serotonin 5-HT2C receptor, a moderate-efficacy partial agonist of the serotonin 5-HT2B receptor, and a partial to full agonist of the serotonin 5-HT2A receptor.[8][9][10] The drug shows similar potency in activating the serotonin 5-HT2C and 5-HT2B receptors and around 10- to 30-fold lower relative potency in activating the serotonin 5-HT2A receptor.[8][9][10] It also shows low affinity for the serotonin 5-HT1A and 5-HT1B receptors.[11] The comprehensive receptor interactions of MK-212 have been studied.[12]

In a 1977 study by Clineschidt and colleagues, they dosed mice with varying concentrations of MK-212, and observed its effects.[13] The result correlated very well to binding of indolealkylamine receptors, such as the serotonin and tryptamine receptors, which shows four characteristics. Namely, increased frequency of muscle twitching, head twitches,[13][8] "an increase in the strength of the crossed extensor reflex in the acutely spinalized rat", and the cause of complex motor syndrome.[13] In a later study, MK-212 dose-dependently induced the head-twitch response when combined with the selective serotonin 5-HT2C receptor antagonist SB-242084.[10] In contrast to the preceding findings, MK-212 has been found to dose-dependently suppress the head-twitch response induced by the serotonergic psychedelic DOI, suggesting that serotonin 5-HT2C receptor activation may inhibit the head-twitch response.[14]

History

MK-212 was first described in the scientific literature by 1977.[13][15]

See also

References

  1. ↑ "MK-212: a serotonin-like agonist in the CNS". General Pharmacology 10 (4): 287–290. 1979. doi:10.1016/0306-3623(79)90054-5. PMID 488663. 
  2. ↑ 2.0 2.1 "Prolactin and cortisol responses to MK-212, a serotonin agonist, in obsessive-compulsive disorder". Archives of General Psychiatry 47 (9): 833–839. September 1990. doi:10.1001/archpsyc.1990.01810210041006. PMID 2203327. 
  3. ↑ "Serotonergic 5-HT2C receptors as a potential therapeutic target for the design antiepileptic drugs". Curr Top Med Chem 5 (1): 59–67. 2005. doi:10.2174/1568026053386980. PMID 15638778. 
  4. ↑ "Selective and nonselective serotonin antagonists block the aversive stimulus properties of MK212 and m-chlorophenylpiperazine (mCPP) in mice". Neuropharmacology 49 (8): 1210–1219. December 2005. doi:10.1016/j.neuropharm.2005.07.015. PMID 16165167. 
  5. ↑ 5.0 5.1 5.2 "Stimulation of serum cortisol and prolactin secretion in humans by MK-212, a centrally active serotonin agonist". Biol Psychiatry 23 (8): 818–828. April 1988. doi:10.1016/0006-3223(88)90070-4. PMID 3365458. "The effects of MK-212 [6-chloro-2-(1-piperazinyl)-pyrazine] (10, 20, and 40 mg, orally), a centrally acting serotonin (5-HT) receptor agonist and placebo, on serum cortisol, prolactin, and growth hormone levels were studied in eight healthy men over 3-hr. [...] MK-212 was generally well tolerated by the subjects. Headache and nausea were observed at the higher doses, [...] It has been suggested that 5-HT2 receptor mechanisms may be involved in the mechanism of action of hallucinogenic agents (Glennon et al. 1984). None of the subjects reported hallucinations following any dose of MK-212. Interestingly, on occasion, alcoholic patients given a 20-mg dose of MK-212 have reported that MK-212 produces an LSD-like effect (Meltzer et al. unpublished observations). However, in rats trained to discriminate MK-212 from saline, LSD did not completely substitute for MK-212 (Cunningham et al. 1986). In addition, ketanserin failed to block the discriminative stimulus properties of MK-212.". 
  6. ↑ "Effect of the serotonin agonist, MK-212, on body temperature in schizophrenia". Biol Psychiatry 31 (5): 460–470. March 1992. doi:10.1016/0006-3223(92)90258-2. PMID 1581424. 
  7. ↑ "The effect of apomorphine, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) and placebo on smooth pursuit gain and corrective saccades in normal subjects". Neuropsychopharmacology 11 (1): 49–62. August 1994. doi:10.1038/npp.1994.35. PMID 7945744. 
  8. ↑ 8.0 8.1 8.2 8.3 "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". Br J Pharmacol 128 (1): 13–20. September 1999. doi:10.1038/sj.bjp.0702751. PMID 10498829. 
  9. ↑ 9.0 9.1 9.2 "Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors". Br J Pharmacol 136 (4): 510–519. June 2002. doi:10.1038/sj.bjp.0704747. PMID 12055129. 
  10. ↑ 10.0 10.1 10.2 10.3 "Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists". Pharmacol Biochem Behav 69 (3-4): 643–652. 2001. doi:10.1016/s0091-3057(01)00552-4. PMID 11509227. 
  11. ↑ "Functional correlates of serotonin 5-HT1 recognition sites". J Recept Res 8 (1–4): 59–81. 1988. doi:10.3109/10799898809048978. PMID 3290473. 
  12. ↑ "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron 113 (19): 3129–3142.e9. July 2025. doi:10.1016/j.neuron.2025.06.012. PMID 40683247. https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf. 
  13. ↑ 13.0 13.1 13.2 13.3 "Central serotonin-like activity of 6-chloro-2-[1-piperazinyl]-pyrazine (CPP; MK-212)". European Journal of Pharmacology 44 (1): 65–74. July 1977. doi:10.1016/0014-2999(77)90117-0. PMID 885160. 
  14. ↑ "Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice". Br J Pharmacol 101 (3): 667–673. November 1990. doi:10.1111/j.1476-5381.1990.tb14138.x. PMID 2150180. 
  15. ↑ "Anorexigenic and ancillary actions of MK-212 (6-chloro-2-(1-piperazinyl)-pyrazine; CPP)". Psychopharmacology (Berl) 55 (1): 27–33. November 1977. doi:10.1007/BF00432813. PMID 414258. 



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