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-NH 2 (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 Trp 30 residue to investigate structural features of SNF 9007 that would distinguish between binding requirements in this region for the CCK-B and 6-opioid receptors. Thus, the four optically pure isomers of β-MeTrp were substituted for L-Trp 30 of SNF 9007. Receptor binding results suggest that the preferred topography of the Trp 30 residue for CCK-B receptor binding may be the 2S,3S (erythro-L) configuration whereas for the 6-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-6 opioid receptor template model (Nikiforovich et al. Biopolymers 1991, 31, 941-955).