To improve our knowledge of the bioactive conformation of CCK(1) antagonists, we previously described that replacement of the alpha-MeTrp residue of dipeptoids with the (2S,5S, 11bR)-2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carbox ylate (IBTM) skeleton, a probed type II' beta-turn mimetic, led to restricted analogues (2S,5S,11bR,1'S)- and (2S,5S,11bR, 1'R)-2-(benzyloxycarbonyl)amino-5-[1'-benzyl-2'-(carboxy)ethyl]carbam oyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole, 1a,b, showing high binding affinity and selectivity for CCK(1) receptors. In this report, we describe the synthesis and binding profile of new analogues of compounds 1 designed to explore the importance of the C-terminal residue and of the type of beta-turn on the receptor binding affinity and selectivity. Structure-affinity relationship studies show that a C-terminal free carboxylic acid and an S configuration of the Phe and betaHph residues are favorable for CCK(1) receptor recognition. Moreover, selectivity for this receptor subtype is critically affected by the beta-turn type. Thus, while compounds 15a and 16a, containing the (2S,5S,11bR)- and (2R,5R, 11bS)-IBTM frameworks, respectively, are both endowed with nanomolar affinity for CCK(1) receptors, restricted dipeptoid derivative 15a, incorporating the type II' IBTM mimetic, shows approximately 6-fold higher CCK(1) selectivity than analogue 16a, with the type II mimetic. From these results, we propose that the presence of a beta-turn-like conformation within the peptide backbone of dipeptoids could contribute to their bioactive conformation at the CCK(1) receptor subtype. Concerning functional activity, compounds 15a and 16a behave as CCK(1) receptor antagonists.

A series of analogues of uridine 5'-diphosphate glucose and uridine 5'-diphosphate glucosamine have been synthesized by reaction of 2,3,4,6-tetra-O-benzyl-, 2,3,4,6-tetra-O-benzoyl-, 2,3,4,6-tetra-O-acetyl-, and 2,3,4,6-tetra-O-palmitoyl-alpha-D-glucopyranose and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-alpha-D-glucopyranose with chlorosulfonyl isocyanate and 2',3'-O-isopropylideneuridine. Isopropylidene and acetyl groups of the resulting 5'-O-[[[[(alpha-D-glucopyranosyl)oxy]carbonyl]amino]sulfonyl] -2',3'-O-isopropylideneuridine derivatives were removed by reaction with a TFA/water (5:1) mixture and methanolic ammonia, respectively. The 5'-O-[[[[(2",3",4",6"-tetra-O-benzyl-and 2",3",4",6"-tetra-O-benzoyl-alpha-D-glucopyranosyl)oxy]carbonyl] amino]sulfonyl]-2',3'-O-isopropylideneuridine (13 and 19) and the corresponding deisopropylidenated derivatives showed antiviral activity as determined by the inhibition of the cytopathic effect induced by HSV-1 replication and by the plaque assay method. Compound 13 inhibited glycosylation of proteins in HSV-1 infected HeLa cells.

To establish structure-activity relationships a new series of analogues of the highly potent and selective CCK(1) receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) modified at N2-position of the central scaffold has been prepared and evaluated as CCK receptor ligands. With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitro functional activity evaluation suggest the importance of the lipophilic character and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for potent and selective binding and antagonist activity at CCK(1) receptor subtype. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have emerged as more potent and selective CCK(1) receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)-stereochemistry at the central bicyclic skeleton as an essential structural requirement for potent binding to this receptor subtype.