The effect of 17-N substituents on the activity of the opioid κ receptor in nalfurafine derivatives

Naltrindole derivatives with fluorinated ethyl substituents on the 17-nitrogen as δ opioid receptor inverse agonists

“…35 The outcomes suggest that the nitrogen in the quinoline ring, which may interact with the lysine 214 residue in the DOR, 36 would be a determinant pharmacophore to induce the DOR agonistic activity. The observed functional tendencies in partial agonist 1 derivatives resembled those of KOR agonist nalfurafine derivatives 15 and DOR agonist KNT-127 derivatives. 10 With respect to the derivatives possessing agonist activities, it seemed that the weaker the binding affinity, the less effective was the agonistic activity.…”

“…1), 14 and reported that these substitutions led to increased selectivities for the KOR or DOR, respectively, but decreased the binding affinities compared with the parent compounds. 10,15 The agonistic activities of 17-fluoroalkyl derivatives also decreased. 10,15 As our previous investigation dealt with agonists, we next attempted to apply these substitutions to DOR antagonist, naltrindole (NTI) 9,16 and compound 1.…”

“…10,15 The agonistic activities of 17-fluoroalkyl derivatives also decreased. 10,15 As our previous investigation dealt with agonists, we next attempted to apply these substitutions to DOR antagonist, naltrindole (NTI) 9,16 and compound 1. 17 Herein, we report the synthesis of derivatives of NTI and compound 1 with the 17-fluoroethyl and 17-alkyl substituents, which were of similar size to the introduced fluorinated ethyl groups.…”

“…Such tendencies as mentioned above were observed with both nalfurafine and KNT-127 derivatives. 10,15 The tendencies obtained in nalfurafine and KNT-127 derivatives were explained from the viewpoint of the message-address concept. 9,16,19 In a similar way, these observations on 4c-e and 6c-e could be explained.…”

Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

“…The opioid ligands bind with opioid receptors with three main types of pharmacophore bonds: ionic attraction, π–π interaction, and hydrogen bonding, termed the message site . The above obtained potent OX 1 R antagonists were hardly bound with the opioid receptors because of the absence of the basic nitrogen and the phenolic hydroxy group. ,, The ion formed by the protonation on the basic 17-nitrogen and the acidic hydrogen derived from the 3-phenolic hydroxyl group seemed to disrupt the fitting to the orexin receptor. This information could be an important clue for designing OX 1 R ligands with a morphinan skeleton without affinity for opioid receptors.…”