R-96544

R-96544
Clinical data
Other namesR96544; R-96,544; MPM
Drug classSerotonin 5-HT2A receptor antagonist
ATC code
  • None
Identifiers
  • (3R,5R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methylpyrrolidin-3-ol
CAS Number
PubChem CID
ChemSpider
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H29NO3
Molar mass355.478 g·mol−1
3D model (JSmol)
  • CN1C[C@@H](C[C@H]1CCOC2=CC=CC=C2CCC3=CC(=CC=C3)OC)O
  • InChI=1S/C22H29NO3/c1-23-16-20(24)15-19(23)12-13-26-22-9-4-3-7-18(22)11-10-17-6-5-8-21(14-17)25-2/h3-9,14,19-20,24H,10-13,15-16H2,1-2H3/t19-,20-/m1/s1
  • Key:AFZLABYDOCWQBQ-WOJBJXKFSA-N

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. ^ a b c d e f g Ogawa T, Sugidachi A, Tanaka N, Fujimoto K, Asai F (December 2002). "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. doi:10.1016/s0014-2999(02)02654-7. PMID 12464356.
  2. ^ a b c Kumar JS, Prabhakaran J, Erlandsson K, Majo VJ, Simpson NR, Pratap M, et al. (May 2006). "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. 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". AdisInsight. 13 May 2008. Retrieved 22 April 2026.
  4. ^ "Delving into the Latest Updates on R-102444 with Synapse". Synapse. 10 January 2026. Retrieved 22 April 2026.
  5. ^ a b c Anderberg RH, Richard JE, Eerola K, López-Ferreras L, Banke E, Hansson C, et al. (April 2017). "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. doi:10.2337/db16-0755. PMC 6237271. 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. ^ a b c Ogawa T, Sugidachi A, Tanaka N, Fujimoto K, Asai F (February 2004). "Effects of R-102444, an orally active 5-HT2A receptor antagonist, in rat models of peripheral vascular disease". Vascular Pharmacology. 41 (1): 7–13. doi:10.1016/j.vph.2004.03.001. PMID 15135326.
  7. ^ Ogawa T, Sugidachi A, Tanaka N, Fujimoto K, Fukushige J, Tani Y, et al. (October 2005). "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. doi:10.1016/j.ejphar.2005.08.033. PMID 16183055.
  8. ^ Futuro Neto HA, Macedo SM, Silva NF, Cabral AM, Pires JG (March 2011). "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. doi:10.1590/s0100-879x2011007500016. PMID 21344136.
  9. ^ Shioda K, Nisijima K, Yoshino T, Kuboshima K, Iwamura T, Yui K, et al. (November 2008). "Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats". Neurotoxicology. 29 (6): 1030–1036. Bibcode:2008NeuTx..29.1030S. doi:10.1016/j.neuro.2008.07.005. PMID 18722468.
  10. ^ Ding ZM, Toalston JE, Oster SM, McBride WJ, Rodd ZA (June 2009). "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. doi:10.1007/s00213-009-1468-9. PMC 2856072. PMID 19165471.
  11. ^ Katsidoni V, Apazoglou K, Panagis G (February 2011). "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. doi:10.1007/s00213-010-1887-7. PMID 20577718.
  12. ^ Xu ZH, Yang Q, Ma L, Liu SB, Chen GS, Wu YM, et al. (2012). "Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome". PLOS ONE. 7 (10) e48741. Bibcode:2012PLoSO...748741X. doi:10.1371/journal.pone.0048741. PMC 3485341. PMID 23119095.
  13. ^ Biagioni AF, de Freitas RL, da Silva JA, de Oliveira RC, de Oliveira R, Alves VM, et al. (April 2013). "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. doi:10.1016/j.neuropharm.2012.10.024. PMID 23201351.
  14. ^ de Freitas RL, de Oliveira RC, de Oliveira R, Paschoalin-Maurin T, de Aguiar Corrêa FM, Coimbra NC (January 2014). "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. doi:10.1002/syn.21697. PMID 23913301.
  15. ^ de Freitas RL, Medeiros P, da Silva JA, de Oliveira RC, de Oliveira R, Ullah F, et al. (November 2016). "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. doi:10.1016/j.neuroscience.2016.08.040. PMID 27600945.
  16. ^ da Silva Soares R, Falconi-Sobrinho LL, Dos Anjos-Garcia T, Coimbra NC (January 2019). "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. doi:10.1016/j.bbr.2017.07.016. PMID 28736332.
  17. ^ da Silva Soares R, Falconi-Sobrinho LL, Almada RC, Coimbra NC (July 2019). "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. doi:10.1016/j.euroneuro.2019.05.007. PMID 31227263.
  18. ^ Hessel M, Pape HC, Seidenbecher T (October 2020). "Stimulation of 5-HT receptors in anterodorsal BNST guides fear to predictable and unpredictable threat". European Neuropsychopharmacology. 39: 56–69. doi:10.1016/j.euroneuro.2020.08.006. PMID 32873441.
  19. ^ a b Tanaka N, Goto R, Ito R, Hayakawa M, Sugidachi A, Ogawa T, et al. (February 2000). "[2-(omega-phenylalkyl)phenoxy]alkylamines.II: Synthesis and selective serotonin-2 receptor binding". Chemical & Pharmaceutical Bulletin. 48 (2): 245–255. doi:10.1248/cpb.48.245. PMID 10705513.
  20. ^ a b Tanaka N, Goto R, Ito R, Hayakawa M, Sugidachi A, Ogawa T, et al. (November 2000). "[2-(O-Phenylalkyl)phenoxy]alkylamines III: Synthesis and selective serotonin-2 receptor binding (2)". Chemical & Pharmaceutical Bulletin. 48 (11): 1729–1739. doi:10.1248/cpb.48.1729. PMID 11086903.
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