Synthesis of Tripeptides Containing d‑Trp Substituted at the Indole Ring, Assessment of Opioid Receptor Binding and in Vivo Central Antinociception

The noncationizable tripeptide Ac-d-Trp-Phe-GlyNH₂ was recently proposed as a novel minimal recognition motif for μ-opioid receptor. The introduction of different substituents (methyl, halogens, nitro, etc.) at the indole of d-Trp significantly influenced receptor affinities and resulted in serum stability and in a measurable effect on central antinociception in mice after ip administration

Opioid Activity Profiles of Oversimplified Peptides Lacking in the Protonable N‑Terminus

Recently, we described cyclopeptide opioid agonists containing the d-Trp-Phe sequence. To expand the scope of this atypical pharmacophore, we tested the activity profiles of the linear peptides Ac-Xaa-Phe-Yaa (Xaa = l/d-Trp, d-His/Lys/Arg; Yaa = H, GlyNH₂). Ac-d-Trp-PheNH₂ appeared to be the minimal binding sequence, while Ac-d-Trp-Phe-GlyNH₂ emerged as the first noncationizable short peptide (partial) agonist with high μ-opioid receptor affinity and selectivity. Conformational analysis suggested that <b>5</b> adopts in solution a β-turn conformation

Ligand Based Approach to L‑Type Calcium Channel by Imidazo[2,1‑<i>b</i>]thiazole-1,4-Dihydropyridines: from Heart Activity to Brain Affinity

The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo­[2,1-<i>b</i>]­thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo­[2,1-<i>b</i>]­thiazole-1,4-DHPs and their selectivity on Ca_v1.2 and Ca_v1.3 isoforms, we performed binding studies on guinea pig atrial and ventricular membranes on intact cells expressing the cloned Ca_v1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Ca_v1.2 and/or Ca_v1.3, molecular modeling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure–activity relationship of the 4-imidazo­[2,1-<i>b</i>]­thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level