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Optimization of bifunctional piperidinamide derivatives as σ 1 R Antagonists/MOR agonists for treating neuropathic pain.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Dec 15; Vol. 226, pp. 113879. Date of Electronic Publication: 2021 Oct 04. - Publication Year :
- 2021
-
Abstract
- Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ <subscript>1</subscript> R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ <subscript>1</subscript> R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ <subscript>1</subscript> R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114, as a mixed σ <subscript>1</subscript> R/MOR ligand, has potential for treating neuropathic pain.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Acetic Acid
Amides chemical synthesis
Amides chemistry
Animals
Behavior, Animal drug effects
Dose-Response Relationship, Drug
Formaldehyde
Guinea Pigs
Mice
Mice, Inbred ICR
Molecular Dynamics Simulation
Molecular Structure
Neuralgia chemically induced
Neuralgia metabolism
Pain Measurement
Piperidines chemical synthesis
Piperidines chemistry
Rats
Rats, Sprague-Dawley
Receptors, Opioid, mu metabolism
Receptors, sigma metabolism
Structure-Activity Relationship
Sigma-1 Receptor
Amides pharmacology
Neuralgia drug therapy
Piperidines pharmacology
Receptors, Opioid, mu agonists
Receptors, sigma antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 226
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34628236
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113879