Cyclic Dimers Of C-terminal γ2-MSH Analogs As Selective Antagonists Of The Human Sensory Nerve-Specific Receptor (SNSR-4)
Sensory nerve-specific G-protein coupled receptors (SNSR) have been implicated in the transmission of pain based on their unique expression and distribution in CNS and periphery. Human SNSRs are potently activated by pro-enkephalin A gene products such as BAM-22 and BAM(8–22) whereas γ2-MSH derived sequences are the most potent activators of the rat receptor [1,2]. Both families of peptides produce a pro-nociceptive effect in various animal models of pain suggesting that a SNSR antagonist might have potential as an analgesic agent. The low homology between the human and rat receptor and widely different structure-activity relationships (SAR) of the activating ligands prompted the search for selective antagonists for either SNSR.
Starting from the most potent rat receptor agonist, the N-terminal fragment γ2-MSH(6–12), extensive SAR studies were performed yielding linear and cyclic analogs with exclusively agonist activity at the rat receptor while being completely inactive...