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Mixed kappa/mu opioid receptor agonists: the 6 beta-naltrexamines
Gerta Cami-Kobeci1, Adrian P Neal, Faye A Bradbury
1Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.
Journal of Medicinal Chemistry
|March 4, 2009
Summary
New naltrexamine-series ligands were synthesized to target kappa opioid receptors (KOR) and mu opioid receptors (MOR). Two compounds, 12a and 12b, showed distinct in vivo profiles, offering potential for substance abuse treatments.
Area of Science:
- Medicinal Chemistry
- Neuropharmacology
- Drug Discovery
Background:
- Naltrexamine-series ligands exhibit kappa opioid receptor (KOR) agonist activity.
- Varying activity at mu opioid receptor (MOR) has been observed.
- Developing KOR agonist/MOR partial agonist ligands is a therapeutic goal for cocaine abuse.
Purpose of the Study:
- To synthesize and evaluate novel 6 beta-cinnamoylamino derivatives of naltrexamine.
- To identify ligands with a specific KOR agonist/MOR partial agonist profile.
- To explore potential treatments for cocaine abuse.
Main Methods:
- Synthesis of novel naltrexamine derivatives.
- In vitro binding assays to assess receptor affinity and selectivity.
- Functional assays to determine KOR and MOR activity.
- In vivo evaluation of promising ligand candidates.
Main Results:
- All synthesized ligands demonstrated high affinity and nonselective binding in vitro.
- Functional assays confirmed high efficacy KOR agonism with partial MOR agonism.
- In vivo studies showed ligand 12a as a KOR agonist.
- Ligand 12b exhibited predominant MOR agonist activity in vivo.
Conclusions:
- The novel naltrexamine derivatives possess the desired pharmacological profiles.
- Compounds 12a and 12b show distinct in vivo activities.
- These ligands represent potential candidates for further development in treating substance abuse disorders.
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