Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists.

Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead 4a employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as 10a (PW0677), 15b (PW0729), and 24f (PW0866), with improved potency and efficacy. Intriguingly, compounds 10a and 24f showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound 4a, indicating that reducing GPR52 ß-arrestin activity with biased agonism results in sustained GPR52 activation. Further exploration of compounds 15b and 24f indicated improved potency and efficacy, and excellent target selectivity, but limited brain exposure warranting further optimization. These balanced and biased GPR52 agonists provide important pharmacological tools to study GPR52 activation, signaling bias, and therapeutic potential for neuropsychiatric and neurological diseases.

Hipotensión ortostática en enfermedad de Parkinson / Orthostatic hypotension in Parkinson's disease

The current concept of Parkinson’s disease comprises a group of non-motor symptoms: neuropsychiatric disorders, sleep disturbances and dysautonomia, among others. Orthostatic hypotension is a frequent problem that impairs the patient’s quality of life. We review the symptoms of this disorder, its pathogeny and the available diagnostic tools. We emphasize the early suspicion and show the treatment options, based on the available evidence and our experience.