Chemistry:R-96544

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R-96544, also known as MPM, is a serotonin 5-HT2A receptor antagonist which is used in scientific research.[1][2] It is also the active form of the laurate (dodecanoate) ester prodrug R-102444, which was investigated for potential medical use but was never marketed.[1][3][4]

R-96544 shows high affinity for the serotonin 5-HT2A receptor (Ki = 1.6 nM) and is selective for this receptor over various other targets.[1][2][5] However, one exception is that it shows only 4-fold lower affinity for the serotonin 5-HT2C receptor relative to the serotonin 5-HT2A receptor.[1][5] The drug inhibits serotonin-induced platelet aggregation in preclinical research and hence has antiplatelet effects.[1][6] It also inhibits the pressor effects of serotonin in rodents.[1][6] R-96544 is effective as a treatment in animal models of peripheral vascular disease and pancreatitis.[6][7] It can attenuate the bradycardia induced by activation of the Bezold–Jarisch reflex by the serotonin 5-HT3 receptor agonist phenylbiguanide in rodents.[8]

R-96544, similarly to other serotonin 5-HT2A receptor antagonists like ketanserin and ritanserin, blocks the hyperthermia induced by MDMA in rodents.[9] It inhibits ethanol self-administration in rodents.[10] On the other hand, the drug does not affect intracranial self-stimulation (ICSS) in rodents, though it can reverse the suppression of ICSS induced by the serotonin 5-HT2A receptor agonist TCB-2 and by the serotonin 5-HT2C receptor agonist WAY-161503.[11] R-96544 has been found to facilitate long-term potentiation (LTP) in the anterior cingulate cortex (ACC) ex vivo.[12] Application of R-96544 directly to certain brain areas has been found to inhibit fear- and seizure-induced analgesia in rodents.[13][14][15][16][17][18] It inhibits the weight loss induced by the GLP-1 receptor agonist exendin-4 (EX4) in rodents, which appeared to be due specifically due to serotonin 5-HT2A receptor antagonism rather than due to actions at the serotonin 5-HT2C receptor.[5]

The chemical synthesis of R-96544 has been described.[19][20] A radiolabeled form of R-96544, known as [11C]MPM, has been studied as a positron emission tomography (PET) imaging tracer.[2]

R-96544 was first described in the scientific literature by Naoki Tanaka and colleagues by 2000.[1][19][20]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444". European Journal of Pharmacology 457 (2–3): 107–114. December 2002. doi:10.1016/s0014-2999(02)02654-7. PMID 12464356. 
  2. ↑ 2.0 2.1 2.2 "Synthesis and in vivo evaluation of [O-methyl-11C](2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine as a 5-HT2A receptor PET ligand". Nuclear Medicine and Biology 33 (4): 565–574. May 2006. doi:10.1016/j.nucmedbio.2006.02.001. PMID 16720250. "R-102444 ((2R,4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methyl pyrrolidine hydrochloride) is a 5-HT2A receptor antagonist that undergoes bioconversion to the active form, R-96544 ((2R,4R)- 4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine) (13) or MPM, which binds with high affinity to the 5-HT2A receptor after oral administration [19]. The pharmacologic profile of R-96544 has been examined in platelets and smooth muscle from various animal species and in rat brain where it exhibits selectivity for 5-HT2A receptors (Ki=1.6 nM) [20]. MPM has an IC50 (50% inhibitory concentration) of 310, 2400, 3700, >5000 and >5000 nM for α1-adrenergic, D2 dopamine, 5-HT1, 5-HT3 and β-adrenergic receptors, respectively [20].". 
  3. ↑ "R 102444". 13 May 2008. https://adisinsight.springer.com/drugs/800015510. 
  4. ↑ "Delving into the Latest Updates on R-102444 with Synapse". 10 January 2026. https://synapse.patsnap.com/drug/b0b12ecbf94e4711bb4b28870820dc9c. 
  5. ↑ 5.0 5.1 5.2 "Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight". Diabetes 66 (4): 1062–1073. April 2017. doi:10.2337/db16-0755. PMID 28057699. "R-96544 is a potent, selective 5HT2A receptor antagonist; R-96544 shows 100-fold higher affinity for the human 5HT2A receptors than 5HT1A, 5HT1B, 5HT1D, 5HT5A, 5HT6, 5HT7 receptors and 5-HT transporter, although R-96544 has relatively high affinity for 5HT2C receptors (fourfold less compared to 5-HT2A) (21).". 
  6. ↑ 6.0 6.1 6.2 "Effects of R-102444, an orally active 5-HT2A receptor antagonist, in rat models of peripheral vascular disease". Vascular Pharmacology 41 (1): 7–13. February 2004. doi:10.1016/j.vph.2004.03.001. PMID 15135326. 
  7. ↑ "Effects of R-102444 and its active metabolite R-96544, selective 5-HT2A receptor antagonists, on experimental acute and chronic pancreatitis: Additional evidence for possible involvement of 5-HT2A receptors in the development of experimental pancreatitis". European Journal of Pharmacology 521 (1–3): 156–163. October 2005. doi:10.1016/j.ejphar.2005.08.033. PMID 16183055. 
  8. ↑ "Central 5-HT(2A) receptors modulate the vagal bradycardia in response to activation of the von Bezold-Jarisch reflex in anesthetized rats". Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas 44 (3): 224–228. March 2011. doi:10.1590/s0100-879x2011007500016. PMID 21344136. 
  9. ↑ "Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats". Neurotoxicology 29 (6): 1030–1036. November 2008. doi:10.1016/j.neuro.2008.07.005. PMID 18722468. Bibcode: 2008NeuTx..29.1030S. 
  10. ↑ "Involvement of local serotonin-2A but not serotonin-1B receptors in the reinforcing effects of ethanol within the posterior ventral tegmental area of female Wistar rats". Psychopharmacology 204 (3): 381–390. June 2009. doi:10.1007/s00213-009-1468-9. PMID 19165471. 
  11. ↑ "Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine". Psychopharmacology 213 (2–3): 337–354. February 2011. doi:10.1007/s00213-010-1887-7. PMID 20577718. 
  12. ↑ "Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome". PLOS ONE 7 (10). 2012. doi:10.1371/journal.pone.0048741. PMID 23119095. Bibcode: 2012PLoSO...748741X. 
  13. ↑ "Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways". Neuropharmacology 67: 379–394. April 2013. doi:10.1016/j.neuropharm.2012.10.024. PMID 23201351. 
  14. ↑ "The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT₂A and 5-HT₂C serotonergic receptors in post-ictal antinociception". Synapse 68 (1): 16–30. January 2014. doi:10.1002/syn.21697. PMID 23913301. 
  15. ↑ "The μ1-opioid receptor and 5-HT2A- and 5HT2C-serotonergic receptors of the locus coeruleus are critical in elaborating hypoalgesia induced by tonic and tonic-clonic seizures". Neuroscience 336: 133–145. November 2016. doi:10.1016/j.neuroscience.2016.08.040. PMID 27600945. 
  16. ↑ "5-Hydroxytryptamine 2A receptors of the dorsal raphe nucleus modulate panic-like behaviours and mediate fear-induced antinociception elicited by neuronal activation in the central nucleus of the inferior colliculus". Behavioural Brain Research 357-358: 71–81. January 2019. doi:10.1016/j.bbr.2017.07.016. PMID 28736332. 
  17. ↑ "Dorsal raphe nucleus 5-Hydroxytryptamine 2A receptors are critical for the organisation of panic attack-like defensive behaviour and unconditioned fear-induced antinociception elicited by the chemical stimulation of superior colliculus neurons". European Neuropsychopharmacology 29 (7): 858–870. July 2019. doi:10.1016/j.euroneuro.2019.05.007. PMID 31227263. 
  18. ↑ "Stimulation of 5-HT receptors in anterodorsal BNST guides fear to predictable and unpredictable threat". European Neuropsychopharmacology 39: 56–69. October 2020. doi:10.1016/j.euroneuro.2020.08.006. PMID 32873441. 
  19. ↑ 19.0 19.1 "[2-(omega-phenylalkyl)phenoxy]alkylamines.II: Synthesis and selective serotonin-2 receptor binding". Chemical & Pharmaceutical Bulletin 48 (2): 245–255. February 2000. doi:10.1248/cpb.48.245. PMID 10705513. 
  20. ↑ 20.0 20.1 "[2-(O-Phenylalkyl)phenoxy]alkylamines III: Synthesis and selective serotonin-2 receptor binding (2)". Chemical & Pharmaceutical Bulletin 48 (11): 1729–1739. November 2000. doi:10.1248/cpb.48.1729. PMID 11086903. 



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