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Evaluation of SYA16263 as a new potential antipsychotic agent without catalepsy.

ABSTRACT: SYA16263 exhibited moderate radioligand binding affinity at the D2 receptor and produced inhibition of apomorphine-induced climbing behavior in mice with an ED50 value of 3.88?mg/kg IP, predicting potential antipsychotic effects in humans. Analysis of plasma and brains from rats injected IP with SYA16263 over the course of 24?h revealed a log [brain]/[plasma] (log BB) at Cmax observed equal to 1.08, indicating that SYA16263 enters the brain and is predicted to cross the blood brain barrier (BBB) readily. When tested in animal behavior tests for catalepsy, SYA16263 did not produce catalepsy at doses up to 19 times the apomorphine ED50 value predicting little or no extra-pyramidal (EPS) side effects in humans. This is similar to aripiprazole, which is associated with a low incidence of EPS in humans, but unlike haloperidol which is known to cause severe EPS in humans. Functional activities for SYA16263 show that it acts as a D2 agonist at both the Gi and ?-arrestin pathways, similar to, but better than aripiprazole, which could account for the absence of the catalepsy observed. Taken together, the receptor binding profile, the functional status, the animal behavioral tests and the log BB value, all provide evidence for further pre-clinical testing of SYA16263 as a potential antipsychotic agent with an interesting profile and a unique mechanism of action resulting in no EPS even up to 19 times the ED50 value.

SUBMITTER: Bricker BA

PROVIDER: S-EPMC6581196 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Evaluation of SYA16263 as a new potential antipsychotic agent without catalepsy.

Bricker Barbara A BA Peprah Kwame K Kang Hye J HJ Ablordeppey S Y SY

Pharmacology, biochemistry, and behavior 20190212

SYA16263 exhibited moderate radioligand binding affinity at the D<sub>2</sub> receptor and produced inhibition of apomorphine-induced climbing behavior in mice with an ED<sub>50</sub> value of 3.88 mg/kg IP, predicting potential antipsychotic effects in humans. Analysis of plasma and brains from rats injected IP with SYA16263 over the course of 24 h revealed a log [brain]/[plasma] (log BB) at Cmax observed equal to 1.08, indicating that SYA16263 enters the brain and is predicted to cross the blo ...[more]

PMID: 30768942

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Project description:BackgroundOne of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids.MethodsA series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay.ResultsA series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01-0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488.ConclusionsMethods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

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Evaluation of SYA16263 as a new potential antipsychotic agent without catalepsy.

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Evaluation of SYA16263 as a new potential antipsychotic agent without catalepsy.

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