| Autor: |
Journigan VB; Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi , University, Mississippi 38677, United States., Mésangeau C, Vyas N, Eans SO, Cutler SJ, McLaughlin JP, Mollereau C, McCurdy CR |
| Abstrakt: |
Neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R), and their endogenous ligand NPFF, are one of only several systems responsible for mediating opioid-induced hyperalgesia, tolerance, and dependence. Currently, no small molecules displaying good affinity or selectivity for either subtype have been reported, to decipher the role of NPFF2-R as it relates to opioid-mediated analgesia, for further exploration of NPFF1-R, or for medication development for either subtype. We report the first nonpeptide small molecule scaffold for NPFF1,2-R, the guanidino-piperidines, and SAR studies resulting in the discovery of a NPFF1 agonist (7b, K(i) = 487 ± 117 nM), a NPFF1 antagonist (46, K(i) = 81 ± 17 nM), and a NPFF2 partial antagonist (53a, K(i) = 30 ± 5 nM), which serve as leads for the development of pharmacological probes and potential therapeutic agents. Testing of 46 alone was without effect in the mouse 48 °C warm-water tail-withdrawal test, but pretreatment with 46 prevented NPFF-induced hyperalgesia. |
