2. Academic Validation
  3. Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications

Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications

  • Bioorg Med Chem Lett. 2023 Aug 15:92:129405. doi: 10.1016/j.bmcl.2023.129405.
Alok Nerurkar 1,  Thomas Nguyen 1,  Sheldon Wang 1,  Ulhas Bhatt 1,  Kevin Li 1,  Yihong Li 1,  Pingyu Ding 1,  Frederick J Seidl 1,  Martin Holan 1,  John Lee 1,  Tien Widjaja 1,  Zhi-Liang Wei 1,  Corinne Sadlowski 1,  David Sperandio 1,  Lawrence R McGee 1,  Beth Youngblood 2,  Neil Schwartz 2,  Donald Gehlert 2,  Julio C Medina 3
Affiliations

Affiliations

  • 1 R2M Pharma, Inc., 600 Gateway Blvd. Suite 100, South San Francisco, CA 94080, USA.
  • 2 Epiodyne, 953 Indiana St. San Francisco, CA 94107, USA.
  • 3 R2M Pharma, Inc., 600 Gateway Blvd. Suite 100, South San Francisco, CA 94080, USA. Electronic address: medinaj@r2mpharma.com.
PMID: 37414346 DOI: 10.1016/j.bmcl.2023.129405
Abstract

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.

Keywords

Analgesia; CNS Penetration; Opioid Use Disorder; SAR; µ-Opioid Receptor.

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