Analogues of cholecystokinin 26–33 selective for B-type CCK receptors possess δ opioid receptor agonist activity in vitro and in vivo: Evidence for similarities in CCK-B and δ opioid receptor requirements

The Use of Topographical Constraints In Receptor Mapping: Investigation of the Topographical Requirements of the Tryptophan 30 Residue for Receptor Binding of Asp-Tyr-d-Phe-Gly-Trp-(N-Me)Nle-Asp-Phe-NH2(SNF 9007), a Cholecystokinin (26−33) Analogue That Binds to both CCK-B and δ-Opioid Receptors

“…16 As mentioned earlier, the highly potent CCK-B ligand SNF 9007 (1, Table 1) binds to δ-opioid receptors and can produce analgesia. 8 Evidence suggesting that CCK-B and δ-opioid receptors may have overlapping topographical structural requirements for their agonist ligands was presented recently, 9 and the Trp 30 residue appears to play a critical role.…”

“…Pharmacological results of SNF 9007 ( 1 ) suggest a relationship between the ligand requirements of CCK-B and δ-opioid receptors, which further implies a possible structural relationship between these receptors. , In a case of a peptidic ligand like 1 which interacts with two types of vastly different biological receptors such as the CCK-B and the δ-opioid receptors, the topography of the side chain groups can be expected to play an important role in distinguishing between the binding sites of different receptor types. , Previous reports indicate that the tryptophan residue of CCK is a critical pharmacophore for CCK receptor recognition and binding − with very limited tolerance for modification of the residue. We describe herein an investigation of the topographical surfaces of the tryptophan side chain in SNF 9007 ( 1 ) that may be involved in receptor recognition and potent binding and which help distinguish binding requirements for the CCK-B and δ-opioid receptors.…”

Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain

“…Several studies have shown that descending facilitation from the RVM is driven endogenously by CCK (Kovelowski et al, 2000; (Friedrich and Gebhart, 2003) and that inhibition is regulated by GABAergic interneurons (Cho and Basbaum, 1991; Gilbert and Franklin, 2001; Heinricher et al , 1991; Kovelowski et al , 2000; Moreau and Fields, 1986). CCK and opioid receptors as well as the associated endogenous peptides are not only co-localized in many of the pain modulating areas of the CNS (Ghilardi et al , 1992; Zhang et al , 2009), but also share some structural and pharmacological similarities (Hruby et al , 1994; Slaninova et al , 1991). Here we demonstrate, in rats with SNL, that morphine given spinally lacks efficacy for mechanical hypersensitivity after nerve ligation.…”

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

“…They hypothesized that compounds with mixed opioid agonist activity and balanced CCK1/CCK2 antagonist activity could be a valuable treatment for neuropathic pain. This assumption is based on the following pharmacological and structural facts: i) CCK reduces the antinociceptive effects of opioids [27]; ii) Acute blockade of CCK receptors enhances the antinociceptive potency of morphine and prevents the tolerance to opioids [28]; iii) Injuries to peripheral nerves or sustained administration of morphine induce upregulation of endogenous CCK [29]; iv) CCK and endogenous opioids and their respective receptors have overlapping distribution in the central nervous system [30]; v) In three dimensional models, opioid and CCK receptor pharmacophores share interesting topographical similarities [31]. With the information above and the structures of opioid and CCK peptides, authors undertake the de novo design of bifunctional peptides able to overlap opioid and CCK pharmacophores.…”