An In Vitro and In Vivo study of BNAP: A Novel Peripherally Selective μ‐opioid Receptor Antagonist

• DOI: 10.1096/fasebj.29.1_supplement.929.2
• Publication Date: 2021-06-21T16:56:56Z
• Authors: D Williams; Y Yuan; D Stevens; Y Zhang; W Dewey; H Akbarali
• Keywords: Nap; Opioid antagonist; μ-opioid receptor

Activation of μ‐opioid receptors (MORs) on enteric neurons during opioid treatment inhibits gastrointestinal peristalsis and leads to constipation. This is the most significant side affect associated with treatment. Peripherally active MOR antagonists can minimize constipation without affecting analgesia. Previously, we described 6β‐Naltrexamine derivative NAP as a novel peripherally selective antagonist. was 300x more potent than methylnaltrexone at improving intestinal motility in morphine tolerant mice. However, partially antagonized antinociception mouse tail‐flick assay. Efforts reduce CNS activity led development BNAP. Radioligand binding studies show BNAP maintained high affinity (K­ i = 0.76 ± 0.09 nM). In tail flick assay (10mg/kg) did not antagonize morphine‐induced antinociception. also competitively inhibited contractions circular muscle preparations from distal proximal colon. Both equal efficacy doses tested (1, 10, 100 Interestingly, they were 10x suggests differences receptor density or splice variants between conclusion, antagonist has potency isolated tissue preparations. Thus, suitable lead for further study Supported by DA024009, DA024002, DA007027.