THE USE OF TOPOGRAPHICAL CONSTRAINTS IN RECEPTOR MAPPING - INVESTIGATION OF THE TOPOGRAPHICAL REQUIREMENTS OF THE TRYPTOPHAN-30 RESIDUE FORRECEPTOR-BINDING OF ASP-TYR-D-PHE-GLY-TRP-(N-ME)NLE-ASP-PHE-NH2 (SNF-9007), A CHOLECYSTOKININ(26-33) ANALOG THAT BINDS TO BOTH CCK-B AND DELTA-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 delta-opioid receptors. Pharmacological studies of SNF 9007 suggest a relationship between the ligand require ments of CCK-B and delta-opioid receptors, which further implies a pos sible structural relationship between these receptors. We have utilize d topographical constrainment of the important Trp(30) residue to inve stigate structural features of SNF 9007 that would distinguish between binding requirements in this region for the CCK-B and delta-opioid re ceptors, Thus, the four optically pure isomers of beta-MeTrp were subs tituted for L-Trp(30) Of SNF 9007. Receptor binding results suggest th at the preferred topography of the Trp(30) residue for CCK-B receptor binding may be the 2S,3S (erythro-L) configuration whereas for the del ta-opioid receptor it may be the 2S,3R (threo-L) configuration. Molecu lar modeling studies of these ligands further support the recently rev ised receptor-bound model for CCK-B octapeptide ligands (Kolodziej et al. J. Med. Chem. 1995, 38, 137-149) and are in good agreement with th e DPDPE-delta opioid receptor ''template'' model (Nikiforovich et al. Biopolymers 1991, 31, 941-955).