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

The cholecystokinin (26-33) [CCK (26-33)] octapeptide analog Asp-Tyr-D- Phe-Gly-Trp(N-Me)-Nle-Asp-Phe-NH₂ (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. Pharmacological studies of SNF 9007 suggest a relationship between the ligand requirements of CCK-B and δ-opioid receptors, which further implies a possible structural relationship between these receptors. We have utilized topographical constrainment of the important Trp³⁰ residue to investigate structural features of SNF 9007 that would distinguish between binding requirements in this region for the CCK-B and δ-opioid receptors. Thus, the four optically pure isomers of β-MeTrp were substituted for L-Trp³⁰ of SNF 9007. Receptor binding results suggest that the preferred topography of the Trp³⁰ residue for CCK-B receptor binding may be the 2S,3S (erythro-L) configuration whereas for the δ-opioid receptor it may be the 2S,3R(threo-L)configuration. Molecular modeling studies of these ligands further support the recently revised receptor-bound model for CCK-B octapeptide ligands (Kolodziej et al. J. Med. Chem. 1995, 38, 137-149) and are in good agreement with the DPDPE-δ opioid receptor 'template' model (Nikiforovich et al. Biopolymers 1991, 31,941-955).