Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt¹-DALDA: Effect on Opioid Activity and Biodistribution

Abstract

The influence of the side chain charges of the second and fourth amino acid residues in the peptidic μ opioid lead agonist Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt1]-DALDA and to investigate the Phe3 side chain flexibility, the final amide bond was N-methylated and Phe3 was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (i.p. and s.c.) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity and transport properties. Strikingly, while [Dmt1]-DALDA and its N-methyl analogue, Dmt-D-Arg-Phe-NMeLys-NH2, showed a long-lasting antinociceptive effect (>7h), the peptides with D-Cit2 generate potent antinociception more rapidly (maximal effect at 1h post-injection) but also lose their analgesic activity faster, when compared to [Dmt1]-DALDA and [Dmt1,NMeLys4]-DALDA.

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

“…The increase was also apparent in the pA 2 values (pA 2 ( 21 ) 6.04 → pA 2 ( 22 ) 6.44). In a previous study, 39 we demonstrated that D-Arg 2 could be replaced by D-Cit, a modification that removes one positive charge in the peptide, without loss of BBB permeability. Hence, this modification was also carried out in the present study, to give 23 .…”

Blood–brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins

“…Moreover, 125 I-LinS showed a relatively high liver uptake (15 min after iv injection), which was approximately three times higher compared to the other investigated enkephalins. Several studies have demonstrated that a decrease in the overall lipophilicity of liver targeting peptides suppresses their hepatic uptake [34,40]. LinS was predicted to be more lipophilic than the other three investigated enkephalin analogs, and thus this more lipophilic nature may contribute to the observed higher liver uptake and most likely also to the observed higher real brain penetration (besides active transport systems).…”

“…A rapidly growing body of evidence shows that many peptides, especially endogenous peptide analogs, do cross the BBB based on favorable chemical, physicochemical, and biological properties, including size, flexibility, biochemical properties of amino acids, lipophilicity, hydrogen-bonding, and 3D-conformation. Biomolecular adjustments of the lipophilic nature [7], charge, and H-bonding potential [17], is one strategy applied to improve the BBB permeability and deliverance of therapeutic peptides to the brain [40]. Passive diffusion as well as active transport mechanisms are addressed by this strategy.…”

Investigational peptide and peptidomimetic μ and δ opioid receptor agonists in the relief of pain

“…Novoa et al [36] studied the effect of variation of the net charge, lipophilicity and side chain flexibility in Dmt 1 -DALDA ( 58 , Table 4) on opioid activity and biodistribution. [37].…”