PF-00446687是一种有效的，脑渗透性的，选择性黑皮质素4受体(MC4R)激动剂，EC50为12 ± 1nM。
PF-00446687 is a potent, selective melanocortin-4 receptor (MC4R) agonist with EC50 of 12 ± 1 nM[1]. Pf-446687 is brain penetrant[2].
PF-00446687 binds MC4 receptor with a Ki of 27±4 nM. PF-00446687 has a relatively weak activity at the MC1, MC3, and MC5 receptors with EC50s of 1.02±0.30 μM, 1.16±0.35 μM, and 1.98±0.20 μM, respectively. The broad off-target profiles of PF-00446687 are assessed in the CEREP Bioprint wide ligand screening panel, with the most potent binding activities being at the σ receptor (Ki=330 nM), the sodium ion channel (Ki=690 nM), and the muscarinic M2 receptor (Ki=730 nM)[1].
Pf-446687 is highly selective for MC4R and is both brain penetrant and stable in vivo. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small molecule MC4R agonist, Pf-446687, enhances partner preference formation in the prairie vole, but not in the non-monogamous meadow vole[2].
[1]. Lansdell MI, et al. Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans. J Med Chem. 2010 Apr 22;53(8):3183-97. [2]. Modi ME, et al. Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015 Jul;40(8):1856-65.
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