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Graphical abstract Highlights • We discovered a new chemotype, 7-carboxamide morphinan derivatives as opioid antagonist. • This chemotype is suitable for acting on peripherally. • From our results, compounds which have over 100 of PSA values are difficult to pass BBB. • Naldemedine showed dual actions in one dose, inhibiting constipation and nausea/vomiting induced by opioids. Abstract Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood–brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate. [ABSTRACT FROM AUTHOR]

[Display omitted] P2X 3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X 3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X 3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X 3 receptors (IC 50 , 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X 3 IC 50 , 16.1 nM; P2X 2/3 IC 50 , 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED 50 , 3.1 mg/kg). [ABSTRACT FROM AUTHOR]

• Pyrropyrazolone derivatives as a P2X3 receptor antagonist were synthesized. • The SAR studies were started from hit compound 3 with reference to the previous reported SAR studies from hit compound 1. • Orally bioavailable compound (S)- 42 was discovered. • Compound (S)- 42 showed the analgesic effect almost same as pregabalin by increasing the dosage. The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3 , the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1 , we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration. [ABSTRACT FROM AUTHOR]