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Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy ?-Opioid Receptor (MOR)/?-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

ABSTRACT: We previously reported a novel SAR campaign that converted a metabolically unstable series of ?-opioid receptor (MOR) agonist/?-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporation of an aromatic ring into the pendant enhanced MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired opioid profile in vitro, possessed metabolic half-lives of greater than 1 h in mouse liver microsomes (MLMs), and were active antinociceptive agents in the acetic acid stretch assay (AASA) at subcutaneous doses of 1 mg/kg.

SUBMITTER: Henry S

PROVIDER: S-EPMC7047604 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

Henry Sean S Anand Jessica P JP Twarozynski Jack J JJ Brinkel Ashley C AC Pogozheva Irina D ID Sears Bryan F BF Jutkiewicz Emily M EM Traynor John R JR Mosberg Henry I HI

Journal of medicinal chemistry 20200210 4

We previously reported a novel SAR campaign that converted a metabolically unstable series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporati ...[more]

PMID: 31986033

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Project description:The acute and chronic effects of alcohol on the brain and behavior are linked to alterations in inhibitory synaptic transmission. Alcohol's most consistent effect at the synaptic level is probably a facilitation of γ-aminobutyric acid (GABA) release, as seen from several rodent studies. The impact of alcohol on GABAergic neurotransmission in human neurons is unknown, due to a lack of a suitable experimental model. Human neurons can also be used to model effects of genetic variants linked with alcohol use disorders (AUDs). The A118G single nucleotide polymorphism (SNP rs1799971) of the OPRM1 gene encoding the N40D (D40 minor allele) mu-opioid receptor (MOR) variant has been linked with individuals who have an AUD. However, while N40D is clearly associated with other drugs of abuse, involvement with AUDs is controversial. In this study, we employed Ascl1-and Dlx2-induced inhibitory neuronal cells (AD-iNs) generated from human iPS cell lines carrying N40D variants, and investigated the impact of ethanol acutely and chronically on GABAergic synaptic transmission. We found that N40 AD-iNs display a stronger facilitation (versus D40) of spontaneous and miniature inhibitory postsynaptic current frequency in response to acute ethanol application. Quantitative immunocytochemistry of Synapsin 1+ synaptic puncta revealed a similar synapse number between N40 and D40 iNs, suggesting an ethanol modulation of presynaptic GABA release without affecting synapse density. Interestingly, D40 iNs exposed to chronic intermittent ethanol application caused a significant increase in mIPSC frequency, with only a modest enhancement observed in N40 iNs. These data suggest that the MOR genotype may confer differential sensitivity to synaptic output, which depends on ethanol exposure time and concentration for AD-iNs and may help explain alcohol dependence in individuals who carry the MOR D40 SNPs. Furthermore, this study supports the use of human neuronal cells carrying risk-associated genetic variants linked to disease, as in vitro models to assay the synaptic actions of alcohol on human neuronal cells.

Dataset Information

Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy ?-Opioid Receptor (MOR)/?-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

Publications

Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

Similar Datasets

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