Novel small molecule antagonists of neuropeptide FF1 receptor as potential therapy for neuropathic pain

The amidated neuropeptide FF (NPFF) was originally characterized as a modulator of the endogenous opioid system. NPFF and its related peptides are widely expressed in the CNS and have been shown to be involved in modulating pain sensitivity, endocrine functions, and food intake. Two human receptors for NPFF (FF1 and FF2) have been identified. Ligand binding studies have shown that both receptors are widely distributed in brain. To date the specific role of FF1 and FF2 has not been elucidated, mainly due to the lack of selective ligands for these receptors. In the present investigation we highlight several selective non-peptide antagonists from different structural classes for the FF1 receptor. We demonstrate the selectivity of these compounds as antagonists at FF1 over FF2 in vitro using RSAT, cAMP and binding assays. Moreover, we show that these compounds are active in vivo. Systemic administration of selective FF1 receptor antagonists dose-dependently alleviated tactile hypersensitivity induced by ligat...