I have before described one another agonist and antagonist homobivalent ligands concentrating on the brand new melanocortin receptor program
Overall performance
40–41 Ligands targeting the melanocortin system have been implicated as potential therapeutics or used as pharmacological probes for a wide range of disease states including cancer, 42–46 skin pigmentation disorders, 47 social disorders, 48–49 sexual function disorders, 50–52 Alzheimer’s disease, 53–54 cachexia, 55–59 and obesity. 40, 60–62 All five melanocortin receptor subtypes (MC1-5R) signal through the G?s protein signaling pathway. In this pathway, an agonist binding to the GPCR activates cAMP signal transduction pathways and also results in the recruitment of ?-arrestin. 63 The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) in particular have been elucidated to play roles in energy homeostasis. 60–62, 64–65 Ligands for the MC4R were under intense clinical development to treat obesity and related metabolic disorders; however these ligands were reported to have undesirable effects such as increasing blood pressure 66 or inducing male erections. 67 It is hypothesized that ligands that target melanocortin homodimers may have unique effects from the current monovalent approaches, and may, therefore circumvent some side effects.
We have previously revealed you to definitely a keen agonist homobivalent ligand supplies a beneficial collection of during the vivo pharmacological profile compared to the monovalent counterpart suggesting one to emphasizing putative melanocortin dimers could have emotional relevancy. 41 Also, biased ligands is beneficial pharmacological probes so you can elucidate and therefore signaling path is in charge of various melanocortin created consequences (we.age. Weiterlesen