AI Article Synopsis
- Existing antipsychotics do not effectively manage cognitive impairments in schizophrenia and can cause serious side effects.
- Trace amine-associated receptor 1 (TAAR1) is identified as a promising target for new antipsychotic drugs that could potentially avoid these side effects.
- A new series of TAAR1 agonists were developed, showing effectiveness in alleviating schizophrenia-like symptoms in rodent models without causing unwanted side effects, positioning them as potential candidates for future schizophrenia treatments.
Article Abstract
The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, displayed a potent TAAR1-G/G dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-G pathway activation. In rodent models, significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, exhibited favorable pharmacokinetic ( = 2.31 h, = 39%) and safety properties. All these demonstrated that may be used as a novel drug candidate for schizophrenia treatment.
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| http://dx.doi.org/10.1021/acs.jmedchem.4c00195 | DOI Listing |
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