Functional Activity to Kappa Opioid Receptor

Binding Affinity and Selectivity and Functional Activity to Kappa Opioid Receptor

Difelikefalin has a high selectivity for kappa receptors over other opioid receptors and has no affinity for non-opioid receptors. There is no detectable activity at mu or delta-opioid receptors. Kappa opioid receptors and endogenous ligands, dynorphins are expressed and elevated in inflammation, making them potential targets for difelikefalin (Lattanzi, 2018). Difelikefalin physicochemistry properties showed that it could not pass through the brain barriers and hence has no deleterious effect on the central nervous system. Difelikefalin is consists of non-natural d-amino acids forming a tetrapeptide. The amino acids have a higher potency and selectivity for kappa opioid receptors. Difelikefalin undergoes an insignificant metabolism process and does not bind to drug uptake transporters. Difelikefalin has a huge poler surface area and is hydrophilic in nature. The drug cannot penetrate cell membranes by passive diffusion because of its high charge at normal body pH.

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When concentration-dependent radioligand binding assay is used to screen the peptide, tritiated diprenorphine is displaced by helianorphin-1 and 2 with the binding affinity (Ki=97 and 220 nM) respectively. Helianorphin-3 and 4 bind to the KOR with (Ki 3.2 and 2.5μM) which are lower micromolar affinity (Muratspahic et al., 2021). The Kappa Opioid Receptor is a GPCR inhibitor, its activation inhibits adenylyl cyclase and leads to a reduction in cAMP, and this test was carried out in cAMP functional assay. Helianorphin-1 and 2 although they have nanomolar affinities, they activated the KOR fully with similar potency to that of helianorphin-3 and 4 which are micromolar. Examination of effect of sequence of epitopes and size on the KOR pharmacological properties and how the affinity and potency could be improved, dyn A 1-6 and A 1-4 were grafted together with a modified sequence of tetrapeptide of the approved difelikefalin drug peptide. The results showed that, regardless of the sequence of epitomes, alanine replaced the lysine residue in the binding loop to reduce the trypsin inhibitory activity of SFTI-1.37. Two-point radioligand displacement studies were used to examine this binding experiment. The binding affinity of SFTI-1 to KOR was not improved by grafting the hexapeptide and the tetrapeptide. According to Hughes et at., (2013), helianorphin-12 binds to KOR with Ki 2.4μM in a concentration dependent manner and fully activate it with EC50 of 1.4 μM. Dyn A 1-13 in helianorphins have the most promising KOR affinities, they were also modified for the affinity enhancement and substituted the N- terminal YGGF domain of the epitope with the more active tetrapeptides. Helianorphin-19 Binds to the Receptor with Ki 21 nanomolar, 45nanomolar EC50 and 108% Emax, hence it is considered the lead agonist (Muratsapahic et al., 2021). The HEK293 membranes that express KOR and M.O.R. were used to determine the affinity of the epitome for the purpose of assessing the receptor selectivity. It partially displaces tritiated diprenorphine from the binding sites with more than 10 μM Ki value interpreted as greater than 200 times selectivity enhancement for Kappa opioid receptors. 

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