The Antidepressant-like Activity, Effects on Recognition Memory Deficits, Bioavailability, and Safety after Chronic Administration of New Dual-Acting Small Compounds Targeting Neuropsychiatric Symptoms in Dementia.

ABSTRACT

This study aimed to extend the body of preclinical research on prototype dual-acting compounds combining the pharmacophores relevant for inhibiting cyclic nucleotide phosphodiesterase 10 (PDE10A) and serotonin 5-HT1A/5-HT7 receptor (5-HT1AR/5-HT7R) activity into a single chemical entity (compounds PQA-AZ4 and PQA-AZ6). After i.v. administration of PQA-AZ4 and PQA-AZ6 to rats, the brain to plasma ratio was 0.9 and 8.60, respectively. After i.g. administration, the brain to plasma ratio was 5.7 and 5.3, respectively. An antidepressant-like effect was observed for PQA-AZ6 in the forced swim test, after chronic 21-day treatment via i.p. administration with 1 mg/kg/day. Both compounds revealed an increased level of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus and prefrontal cortex. Moreover, PQA-AZ4 and PQA-AZ6 completely reversed (+)-MK801-induced memory disturbances comparable with the potent PDE10 inhibitor, compound PQ-10. In the safety profile that included measurements of plasma glucose, triglyceride, and total cholesterol concentration, liver enzyme activity, the total antioxidant activity of serum, together with weight gain, compounds exhibited no significant activity. However, the studied compounds had different effects on human normal fibroblast cells as revealed in in vitro assay. The pharmacokinetic and biochemical results support the notion that these novel dual-acting compounds might offer a promising therapeutic tool in CNS-related disorders.