Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor

Abstract

Existing pharmacotherapies acting on the opioid receptor system have been extensively used to treat chronic pain and addictive disorders. Nevertheless, the adverse side effects associated with opioid therapy underscore the need for concerted measures to develop safer analgesics. A promising avenue of research stems from the characterization of a sodium-dependent allosteric regulation site housed within the delta-opioid receptor and several other G protein-coupled receptors (GPCRs), thereby revealing the presence of a cluster of sodium and water molecules lodged in a cavity thought to be present only in the inactive conformation of the receptor. Studies into the structure–function relationship of said pocket demonstrated its critical involvement in the functional control of GPCR signaling. While the sodium pocket has been proposed to be present in the majority of class A GPCRs, the shape of this allosteric cavity appears to have significant structural variation among crystallographically solved GPCRs, making this site optimal for the design of new allosteric modulators that will be selective for opioid receptors. The size of the sodium pocket supports the accommodation of small molecules, and it has been speculated that promiscuous amiloride and 5′-substituted amiloride-related derivatives could target this cavity within many GPCRs, including opioid receptors. Using pharmacological approaches, we have described the selectivities of 5′-substituted amiloride-related derivatives, as well as the hitherto undescribed activity of the NHE1 inhibitor zoniporide toward class A GPCRs. Our investigations into the structural features of the delta-opioid receptor and its ensuing signaling activities suggest a bitopic mode of overlapping interactions involving the orthosteric site and the juxtaposed Na + pocket, but only at the active or partially active opioid receptor.

Descriptive molecular pharmacology of the δ opioid receptor (DOR): A computational study with structural approach

“…In our main simulated systems, the Central Coordination System (CCS) displays notable changes in its constitution. As it has been found [ 53 , 118 , 119 ], the sodium cation in the CCS functions as an allosteric inactivator of GPCRs. The conserved residue D 2.50 [ 106 ], along with N310 7.45 and S311 7.41 , plays a pivotal role in the cation coordination, which is a key feature of the Conserved Cationic Site (CCS) in Class A GPCRs.…”

Protease secretions by the invading blastocyst induce calcium oscillations in endometrial epithelial cells via the protease-activated receptor 2

“…However, removal of external Na + did not alter trypsin-induced [Ca 2+ ] I oscillations in mEEC, excluding the potential contribution of ENaC in the [Ca 2+ ] I influx. Possibly, the effect of amiloride on trypsin responses may reflect direct modulation of GPCRs by amiloride, as has been described in earlier studies, especially for the class A GPCRs to which PAR members belong [ 32 , 33 ]. In addition, the lack of voltage-induced currents by whole-cell patch clamp experiments argued against the functional presence of VDCC in mEEC.…”