Invention:
Inventors at the University of Arizona have developed oxytocin analogues which have high potency, are designed to be more stable compared to the native oxytocin hormone (an endogenous peptide which inhibits pain and promotes social connection), have very high selectivity for oxytocin receptors, and are bioavailable for brain therapeutics. These druggable compounds may be further developed for use as non-opioid pain relief, social anxiety, anti-addiction, or post-traumatic stress disorder.
Background:
Opioid drugs like morphine and Oxycontin® are considered to be the gold standard for managing moderate-to-severe pain, and are often used to treat chronic pain as well. Unfortunately, these drugs are plagued with undesired side effects, particularly respiratory depression, GI effects, euphoria and sedation, and the use of these drugs can lead to opioid use disorder (OUD) and fatal overdose. Prescription rates and subsequent addiction, abuse, and hospital admissions for overdose have soared in the past 20 years for opioid drugs, with fentanyl-related abuse and overdose in particular skyrocketing since 2012. Many strategies have been developed to generate efficacious opioids with reduced addiction potential, such as biased ligands, multifunctional ligands, or endogenous peptide derivatives, but none have yet been translated to clinical use. This unsolved limitation of opioids illustrates the great medical need for effective alternative non-opioid analgesics.
An alternate pain modulatory system of great interest is the oxytocin (OT) neuronal network. Extensive research to date has shown that OT modulates pain. Importantly, OT has been shown to inhibit nociceptive pathways in peripheral nerve terminals, in the spinal cord, and in diverse brain pain regulatory systems including the periaqueductal grey, the amygdala, and the anterior cingulate cortex. This pattern is similar to the opioid system, thus explaining the efficacy of OT in modulating pain. Interestingly, modulation of oxytocin receptor (“OXTR”) using an OXTR agonist does not induce the side effects typical of opioid agonists. Opioid receptors and OXTR are neuropeptide receptors, thus given their activities, it is believed that OT can also be used to treat opioid addiction. Furthermore, based on its activity it is believed that OXTR agonists can also be used as non-opioid analgesics. Unfortunately, however, due to the instability of the native disulfide linkage, OT is unsuitable for use as a drug. Moreover, OT cannot readily cross the blood-brain barrier (BBB), so it is generally not well suited for use as a pharmaceutical. Recently, intranasal delivery of native OT has been reported. However, this intranasal delivery method misses important sites of OT action in the spinal cord and periphery. While small molecule OXTR ligands have been developed, they have yet to advance to the clinic.
Applications:
- Non-opioid pain relief
- Opioid Use Disorder (OUD)
- Substance Use Disorder (SUD)
- Autism spectrum disorders
- Asperger's Syndrome
Advantages:
- Derived from endogenous peptide
- Selective to oxytocin receptors
- Increased effectiveness in crossing the blood-brain barrier
- Increased stability in vivo
- Potential for inhalation administration
