3-Methoxylphenylpropyl amides as novel receptor subtype-selective melatoninergic ligands: characterization of physicochemical and pharmacokinetic properties

Abstract

1. Developing subtype-selective melatoninergic ligands has been a subject of considerable interest in drug discovery. A series of 3-methoxyphenylpropyl amide derivatives showing selective binding capacity to type 2 melatonin receptor with subnanomolar range of affinities has been identified recently by our laboratory. In the present study, their physicochemical properties, Caco-2 cell and mdr1-MDCK cell permeability, plasma protein binding, and metabolic stability were investigated.

2. The selected compounds are lipophilic in nature, exhibiting aqueous solubility ranging from 40 to 200 µg/mL. Cell permeability studies on Caco-2 and mdr1-MDCK model revealed that they were readily transported through intestinal epithelium and possessed high penetration potential through blood–brain barrier, implying good oral absorption and central nervous system (CNS) distribution potential. They also showed substantial binding to human plasma protein ranging from 78.5% to 92.3%.

3. These compounds were, however, subjected to rapid cytochrome P450-mediated degradation in rat and human liver microsomes with in vitro half-life of 9.5–31.9 min in rat and 5.5–66.7 min in human, which were much shorter than that of melatonin (∼73 min).

4. Metabolite profiling unveiled that C6-ether linkage and methoxy substituents were likely the major metabolic soft spots in their structures, which provided important information for further improvement of their structural stability.

Keywords::

• Melatonin receptor
• MT2-selective agonist
• permeability
• metabolic stability
• metabolite profiling