Bifunctional μ/δ Opioid Peptides: Variation of the Type and Length of the Linker Connecting the Two Components

摘要: Centrally acting μ opioid agonists like morphine are most widely used in severe pain. However, they produce a number of side effects, including analgesic tolerance, dependence, respiratory depression and inhibition gastrointestinal transit, which often limit their use. It has been shown that selective δ receptor blockade with antagonist reduced the development tolerance dependence (1,2). Furthermore, studies indicated naltrindole reversed alfentanyl (a agonist)-induced (3) enhanced colonic propulsion (4). Taken together, these observations indicate mixed agonist/δ may have low propensity to physical transit. Compared drug combination agonist antagonist, single compound profile is preferable because more predictable pharmacokinetic pharmacodynamic relationship consequence administration medicine (5). The first reported DIPP-NH2[Ψ] (H-Dmt-TicΨ[CH2-NH]-Phe-Phe-NH2), produced potent centrally mediated effect intracerebroventricular (i.c.v.) administration, no somewhat less than (6). A pyridomorphinans also showed (7,8) one them (SoRI 20411) given i.c.v. antinociceptive activity did not tolerance. results provided proof-of-concept for antagonists as candidates effects. limited ability cross blood-brain barrier (BBB). The described above were discovered by chance compounds clear distinction can be made between moieties confer properties molecule responsible behavior. Alternatively, this bifunctional containing distinct components designed. An example chimeric peptide H-Dmt→D-Arg→Phe→Lys→NH-(CH2)2-NH←Phe←Cha[NH-CH2]ΨTic←Tyr-H, component H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1DALDA) (9) H-Tyr-TicΨ[CH2-NH]Cha-Phe-OH (TICP[Ψ] (10) connected "tail-to-tail" via short linker [NH-(CH2)2-NH-] (11) (Figure 1, 2). [Dmt1]DALDA systemically active 2 it plays dual role vector conferring BBB crossing entire construct. Compound nanomolar binding affinity receptors displayed expected vitro (11). Given subcutaneously (s.c.), potency comparable induce (12). Figure 1 Structural formulas μ/δ ligands. In present paper we describe syntheses profiles analogues length α,ω-diaminoalkyl spacer connecting was varied: -NH-(CH2)n-NH- (n = 0, 2, 6 ,8 ,10 ,12) 1–6). Compounds TICP[Ψ] rigid diaminocyclohexane spacers (1R,2R)-(−)-1,2-diaminocyclohexane (compound 7), (1S,2S)-(+)-1,2-diaminocyclohexane 8), cis-1,2-diaminocyclohexane 9) trans-1,4-diaminocyclohexane 10) prepared characterized. tetrapeptide replaced dipeptide H-Dmt-Tic-OH 11) or H-Bcp-Tic-OH (Bcp 4’-N-((4’-phenyl)phenylethyl)carboxamido]phenylalanine) (13) 12) synthesized pharmacologically characterized. It should pointed out interact monovalent fashion either site site, but designed simultaneously bivalent mode both sites heterodimer. Agonist/δ bind mode, such MDAN antagonists, would require much longer (~20 A) (14).