Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Abstract

Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system, where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[DCys-Gly-Trp-Cys]-Asp-Phe-NH 2 ) showed potent binding and agonist activities at δ and µ opioid receptors while displaying some binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

In Vitro Binding Assay of 31Methionine-oxidized Cholecystokinin Octapeptide to the CCKB Receptor

“…[1][2][3][4][5] It was discovered 80 years ago and comprises 33 amino acids; CCK octapeptide (CCK8) and CCK tetrapeptide (CCK4), comprising 8 and 4 amino acids, respectively, have also been identified in living * To whom correspondence should be addressed: Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan. Phe-NH 2 ) accounts for 60% of the CCK family expressed in the human body and exhibits stronger activity than CCK33; in rats, it induces gallbladder contraction and amylase secretion in the pancreatic acini.…”

Topical Cholecystokinin Depresses Itch-Associated Scratching Behavior in Mice

“…Despite their original name of cholecyst stimulators, CCKs have been known to serve as CNS modulators (Dufresne et al, 2006) and CCK8S downmodulates opioid responses (Pommier et al, 2002;Agnes et al, 2008). As suggested in our present study, CCKs may also have a function of downmodulator in the peripheral itch.…”

“…In the brain, sulfated CCK8 (CCK8S) is most abundant (Rehfeld et al, 2007) and possesses one of the strongest endogenous anti-opioid properties (Ma et al, 2006). Prolonged opioid exposure increases the expression of CCKs and CCK2R in the CNS, where CCK8S negatively modulates opioid responses and maintains homeostasis of the opioid system (Pommier et al, 2002;Agnes et al, 2008). Thus, it seems that CCKs are downregulators of opioid-mediated pruritus in CNS.…”

Investigational peptide and peptidomimetic μ and δ opioid receptor agonists in the relief of pain

“…The strategy is similar to opioid agonist/NK1 antagonist strategy. A number of reports are available in the literature focusing on the design, synthesis and SAR study of this class of ligands [82–86]. Hanlon et al [87] studied the in vivo efficacy of novel μ- / δ -opioid agonist/CCK antagonist ligands RSA504 (H-Tyr 1 -D-Nle 2 -Gly 3 -Trp 4 -Nle 5 -Asp 6 -Phe 7 -NH 2 : K i μ = 26 nM, K i δ = 2.6 nM, K i CCK-1 = 9.6 nM, K i CCK-2 = 15 nM; IC 50 μ = 210 nM, IC 50 δ = 23 nM; EC 50 μ = 0.46 nM, EC 50 δ = 4.5 nM; E max μ = 88%, E max δ = 81%), and RSA601 (H-Tyr 1 -D-Phe 2 -Gly 3 -D-Trp 4 - N MeNle 5 -Asp 6 -Phe 7 -NH 2 : K i μ = 5.9 nM, K i δ = 0.42 nM, K i CCK-2 = 1.1 nM; IC 50 μ = 71 nM, IC 50 δ = 24 nM; EC 50 μ = 530 nM, EC 50 δ = 29 nM; E max μ = 50%, E max δ = 14%).…”