ABSTRACT
Opioid use disorders (OUD) are responsible for a major health and socioeconomic crisis in the US,
resulting in more than $500B burden on the economy and more than 47,000 deaths a year due to opioid
overdose. More than 80% of OUD cases started from the use of prescription opioid painkillers, which is
currently the most effective (and often the only available) option for treatment of severe pain. The current
analgesics target ¿-Opioid receptor (MOR), which mediates not only analgesia but also dependence, addiction
leading to OUD, as well as respiratory depression and death. Diversion and misuse of prescription opioid
drugs in US is the key reason for the skyrocketing opioid epidemic. Development of a new generation of
safe and effective analgesics with diminished addiction and abuse potential is desperately needed.
We propose to target peripheral cannabinioid receptor subtype 1 (CB1) as a mechanism to develop
pain relievers devoid of the addiction potential associated with opioid receptors as well as centrally active
CB1 agonists. We propose a bitopic approach targeting the orthosteric site of CB1 to achieve potency and
efficacy and allosteric sodium binding pocket to achieve peripheral over central activity in vivo.
Our long term goal is to develop an orally active CB1 selective agonist with nM potency, poor brain
penetration with optimal drug like properties like protein binding, metabolic stability, no hERG, CYP liability and
oral activity, a goal we will seek to achieve through the U19 mechanism this R34 feeds into. ADME and PK
fine tuning on leads obtained through R34 will be a part of the U19 phase of development.
For this R34 planning grant we bring together a multidisciplinary team with the aim to test if the
bitopic approach can lead to compounds with efficacy in animal models of pain and highly restricted peripheral
activity while showing selectivity for CB1 receptors.
Our optimal compound to be synthesized through this R34 phase will be have the following characteristics:
1) In vitro profile: CB1-agonist with =50 nM potency and 100 fold selectivity over other >350 other targets.
2) DMPK profile: Protein binding<5% free at 10 µM, metabolic stability>2h, hERG>10 µM, CYP
inhibition/activation <20-30% at 10µM and brain:plasma <0.03.
3) In vivo profile: IP/Oral CB1 mediated analgesic, potency ED50=5-10 mg/mg with >2.5h analgesic time
course and lacking central side-effects like abuse potential and other liabilities upto 15xED50 doses.