A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

doi:10.1021/JM00067A004

Paper

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

Published Jul 23, 1993 · A. Naylor, D. Judd, J. Lloyd

Journal of medicinal chemistry

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81

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1

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Abstract

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.

In Vitro Study

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Study Snapshot

4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines show exceptional potency and selectivity as kappa-opioid receptor agonists, with methyl 4-[(3,4-dichlorophenyl)acet

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

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References

Citations

Synthesis of Azabicyclic Isosteres of Piperazine 2S-Carboxylic Acid.

The study developed methods for stereocontrolled synthesis of bicyclic diaza [3.3.0] octane carboxylic acids, providing insights into the relative basicities of nitrogen atoms in these compounds.

Optimization of a Nucleophilic Two-Step Radiosynthesis of 6-O-(2-[18F]fluoroethyl)-6-O-desmethyl-diprenorphine ([18F]FE-DPN) for PET Imaging of Brain Opioid Receptors

Optimizing the synthesis conditions for [18F]FE-DPN enhances its accessibility for PET imaging of brain opioid receptors.

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse.

Kappa opioid receptor agonists effectively treat pain, while antagonists show efficacy in treating anxiety and depression, offering potential new treatments for these disorders.

Synthesis of 8-aminomorphans with high KOR affinity.

The eutomer (1 S,5 R,8 R)- 5a shows high KOR affinity and selectivity over MOR, DOR, and 2 receptors, with a dihedral angle close to the bioactive conformation of flexible KOR agonist 3.

Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography.

Kappa opioid receptor (KOR) neuroimaging using positron emission tomography (PET) has advanced, offering insights into chronic effects of brain disorders and guiding drug selection for maximal therapeutic efficacy.