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.