The C-terminal tetrapeptide amide of gastrin, the shortest sequence of this gastrointestinal hormone capable of exhibiting all the biological properties even though at reduced potency, and the related heptapeptide amide were covalently linked to mono-(6-succinylamino-6-deoxy)-beta-cyclodextrin to analyze the effect of the bulky cyclic carbohydrate moiety on recognition of the peptides by the G-protein-coupled CCK-B/gastrin receptor and on their signal transduction potencies. With the four-carbon succinyl spacer and particularly with the additional tripeptide spacer in the heptapeptide/beta-cyclodextrin conjugate, full recognition by the receptor was obtained with binding affinities identical to those of the unconjugated tetrapeptide and with a potency comparable to that of full agonists. Docking of this conjugate onto a structure of the human CCK-B receptor derived by homology modeling indicates sufficient free space of the peptide moiety for intermolecular interaction at the putative gastrin binding site, whereby additional interactions of the cyclodextrin with the receptor surface apparently suffice for stabilizing the complex and thus for triggering the full hormonal message. The host/guest complexation of the peptide moiety by the beta-cyclodextrin which seems to occur at least in the case of the tetrapeptide conjugate does not suffice in its strength for competing with the receptor recognition. However, multiple presentation of the tetragastrin by its covalent linkage to the heptakis-(6-succinylamino-6-deoxy)-beta-cyclodextrin leads to peptide/peptide and/or peptide/cyclodextrin collapses with strong interferences in the receptor recognition process. Retention of full agonism by suitably designed monoconjugates of bioactive peptides with cyclodextrins suggests a highly promising approach for targeting host/guest complexed or covalently bound cytotoxic drugs to specific tumor cells for receptor-mediated internalization.