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MS1 (drug)

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MS1 (drug)
Clinical data
Drug classμ-Opioid receptor positive allosteric modulator
Identifiers
  • 2-[benzyl-(4-bromophenyl)sulfonylamino]-N-(3-chloro-4-methoxyphenyl)acetamide
PubChem CID
ChemSpider
Chemical and physical data
FormulaC22H20BrClN2O4S
Molar mass523.83 g·mol−1
3D model (JSmol)
  • COC1=C(C=C(C=C1)NC(=O)CN(CC2=CC=CC=C2)S(=O)(=O)C3=CC=C(C=C3)Br)Cl
  • InChI=1S/C22H20BrClN2O4S/c1-30-21-12-9-18(13-20(21)24)25-22(27)15-26(14-16-5-3-2-4-6-16)31(28,29)19-10-7-17(23)8-11-19/h2-13H,14-15H2,1H3,(H,25,27)
  • Key:XILIAVXVRWSRNU-UHFFFAOYSA-N

MS1 is a positive allosteric modulator (PAM) of the μ-opioid receptor (MOR).[1][2][3][4] It was developed from structural modification of the earlier MOR PAM BMS‐986122.[4]

The drug has been found to augment the affinity of the MOR agonist levomethadone ((R)-methadone) for the MOR by 7-fold in vitro and to potentiate activation of the MOR by levomethadone by 4-fold in a G protein assay.[2][1][4] However, MS1 displays strong probe dependence, and while it potentiates the MOR agonists levomethadone and morphine, it had no effect on the affinity or potency of the MOR agonists DAMGO or endomorphin-1.[2][1][4] MS1 shows a preference for β-arrestin recruitment over G protein activation with endomorphin-1 exposure.[3][4] The drug's actions are reportedly similar to those of BMS-986122, though its unclear if their mechanisms of action are the same.[3][4] MS1 shows potentiated analgesic effects with opioids in animals.[2][3][5] It also did not worsen opioid withdrawal symptoms, respiratory depression, or analgesic tolerance.[2][3][5]

MS1 and other atypical MOR activators are of potential interest in the development of novel opioid analgesics with reduced adverse effects and misuse potential.[3][6][7][8] MS1 has notably been found to penetrate the blood–brain barrier in animals.[3] The potential of the related MOR PAMs BMS-986121 and BMS-986122 as pharmaceutical drugs has been restricted owing to their complex chemical synthesis.[3][9][4] MS1 has a much simpler synthesis in comparison and hence has been regarded as having overcome this limitation.[3][9][4]

MS1 was first described in the scientific literature by 2015.[4] Additional MOR PAMs related to MS1, such as Comp5, have been developed.[10][5][4]

References

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  1. ^ a b c Livingston KE, Traynor JR (July 2018). "Allostery at opioid receptors: modulation with small molecule ligands". Br J Pharmacol. 175 (14): 2846–2856. doi:10.1111/bph.13823. PMC 6016636. PMID 28419415.
  2. ^ a b c d e Hovah ME, Holzgrabe U (May 2024). "Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach". Med Res Rev. doi:10.1002/med.22050. PMID 38751227.
  3. ^ a b c d e f g h i Pagare PP, Flammia R, Zhang Y (January 2024). "IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders". Pharmacol Res. 199: 107023. doi:10.1016/j.phrs.2023.107023. PMID 38081336.
  4. ^ a b c d e f g h i j Bisignano P, Burford NT, Shang Y, Marlow B, Livingston KE, Fenton AM, et al. (September 2015). "Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the μ-Opioid Receptor". J Chem Inf Model. 55 (9): 1836–43. doi:10.1021/acs.jcim.5b00388. PMC 4703110. PMID 26347990.
  5. ^ a b c Pryce KD, Kang HJ, Sakloth F, Liu Y, Khan S, Toth K, et al. (September 2021). "A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects". Neuropharmacology. 195: 108673. doi:10.1016/j.neuropharm.2021.108673. PMC 8410669. PMID 34153316.
  6. ^ Yuan Y, Xu T, Huang Y, Shi J (August 2024). "Strategies for developing μ opioid receptor agonists with reduced adverse effects". Bioorg Chem. 149: 107507. doi:10.1016/j.bioorg.2024.107507. PMID 38850778.
  7. ^ Lambert DG (June 2023). "Opioids and opioid receptors; understanding pharmacological mechanisms as a key to therapeutic advances and mitigation of the misuse crisis". BJA Open. 6: 100141. doi:10.1016/j.bjao.2023.100141. PMC 10430815. PMID 37588171.
  8. ^ Varga BR, Streicher JM, Majumdar S (April 2023). "Strategies towards safer opioid analgesics-A review of old and upcoming targets". Br J Pharmacol. 180 (7): 975–993. doi:10.1111/bph.15760. PMC 9133275. PMID 34826881.
  9. ^ a b Remesic M, Hruby VJ, Porreca F, Lee YS (June 2017). "Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics". ACS Chemical Neuroscience. 8 (6): 1147–1158. doi:10.1021/acschemneuro.7b00090. PMC 5689070. PMID 28368571.
  10. ^ González AM, Jubete AG (April 2024). "Dualism, allosteric modulation, and biased signaling of opioid receptors: Future therapeutic potential". Rev Esp Anestesiol Reanim (Engl Ed). 71 (4): 298–303. doi:10.1016/j.redare.2022.06.009. PMID 37683976.
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