<i>C</i>-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics

Abstract

Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.

Discovery of δ Opioid Receptor Full Inverse Agonists and Their Effects on Restraint Stress-Induced Cognitive Impairment in Mice

“…We next assessed the functional activities of the compounds 1d – m , 7a , 7k , 8a , and 8k for the DOR by [ 35 S]­GTPγS binding assays according to the previously reported methods (Table ), and we compared the results to those obtained with the parent DOR antagonists NTI, BNTX, and NTB. The E max values were calculated using the maximum response of reference compounds DPDPE and ICI-174,864 for the compounds with the positive and negative intrinsic activities, respectively.…”

Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives

“…The binding affinities of the synthesized compounds 9 for the opiod receptors were evaluated by competitive binding assays according to the previously reported methods [ 47 ] ( Table 1 ). Although the binding affinity of compound 9d for the DOR was low, the other tested compounds 9 bound to the DOR with strong to moderate affinities.…”

“…As all the tested compounds 9 showed DOR selectivities, we evaluated the functional activities of 9 for the DOR by [ 35 S]GTPγS binding assays according to the previously reported methods [ 47 ] ( Table 1 ). Compounds 9a , 9b , 9f , and 9g showed inverse agonist activities.…”

Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice

“…The binding affinities of the prepared compounds 3a – e , 9b , 9c , 12b , and 12c for the opioid receptors were assessed by competitive binding tests according to the previously reported methods, , and we compared the results of the DOR inverse agonists (ICI-174,864, SYK-165, -619, -656, and -657) (Table ). All the tested compounds showed the highest binding affinities for the DOR among the three opioid receptor types and the low or almost no binding affinities were observed for the MOR and KOR.…”

“…We next evaluated the functional activities of the test compounds 3a – e , 9b , 9c , 12b , and 12c for the DOR by [ 35 S]­GTPγS binding assays according to the previously reported methods , (Table ). For the purpose of comparison, the results of the DOR inverse agonists (ICI-174,864, SYK-165, -619, -656, and -657) are also shown.…”