of Work: The potent delta-opioid receptor anatgonist family of peptides, consisting of the general formula H-Dmt-Tic-NH-CH(R)-R', tested the length and composition of the linker (alkyl, Asp, Asn) (R) and the position of the carboxylate group relative to Bid ((1H-benzimidazole-2-yl) (R') at the C-terminus of Tic. All the compounds exhibited high delta affinities (Ki < 0.1 nM); some analogues had high mu affinities (Ki < 1 nM) depending on the presence or absence of the carboxylate. The bioactivity of several Bid-containing analogues had delta agonism; low to very low mu agonism was detected in these analogues. The data verified the following: chirality of the linker is ineffective; a negative charge affects mu affinity; linker length is critical for the appearance of delta agonist or antagonist activity; and C-terminal extension from Bid also affects the acquisition of these activities. Dmt is the key residue for all these activities. A new series of synthetic Dmt-containing analogues contained bis-Dmt separated by alkyl chains was developed with very high mu affinities (Ki < 0.1 nM), Ke = 3-5 nM, and equipotent with morphine in vivo while the former are ca. 25 times more potent than morphine. Chemical studies on pyrazinone formation revealed an immediate deamination reaction from the aminomethyl group attached to the 1,2-dihyropyrazin-2-one derivative occurred during catalyic hydrogenation was highly site specific. A detailed study on the effect of Dmt incorporation into endomorphin-2 analogues was conducted that verified that the tri- or tetrapeptide containing Dmt was highly potent and that a C-terminal phenethyl group could substitute for Phe-amide. Furthermore, the Dmt-Pro bond was in the cis configuration.
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