Cyclic Biphalin Analogues Incorporating a Xylene Bridge: Synthesis, Characterization, and Biological Profile

Abstract

In this work we enhanced the ring lipophilicity of biphalin introducing a xylene moiety, thus obtaining three cyclic regioisomers. Novel compounds have similar activity as the parent compound, but one of these () shows a remarkable increase of antinociceptive effect. Nociception tests have disclosed its significant high potency and the more prolonged effect in eliciting analgesia, higher than that of biphalin and of the disulfide-bridge-containing analogue ().

Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile

“…In conclusion, the substitution of the disulfide bridge in the first cyclic analogue of biphalin 27 with an olefin bridge leads to geometrical isomer analogues with less affinity at MOR and DOR with respect to the previously reported analogues. 12,13,27 Surprisingly the novel compounds show an increased potency and efficacy in G protein stimulation at MOR, with no observed activation of the DOR. Indeed, our compounds show a slightly improved DOR binding selectivity and a strong analgesic activity higher than that of the cyclic analogue containing D-Pen, 12 in the hot-plate test after i.v.…”

“…These results indicate that the ABAM compounds are MOR agonists/DOR partial antagonists, different from the mixed ΜΟR/DOR agonist activity exerted by biphalin and its cyclic analogues reported in the literature so far. [12][13][14]27 In this work we have described a cyclic biphalin analogue endowed with MOR agonist/DOR partial antagonist activity, which retains a good binding affinity for MOR and DOR, avoiding KOR binding; this latest aspect could be crucial in the design of safer drugs without undesirable side effects, such as tolerance and dependence, that hamper the clinical use of opioid analgesics.…”

Design, synthesis and biological profile of mixed opioid agonist/N-VGCC blocker peptides

“…The same pattern was found for the blocking activity toward Cav2.2 when compared to ziconotide. [22][23][24][25] However, it is worth noting that the improvement of the antinociceptive effect recorded for compound 5a compared with that previously reported for compound 10 in the tail flick test, (Figure 4), may be either related to a higher potency to the Cav2.2 and/or to better tissue penetration and pharmacokinetic. Indeed, the calcium channel blocker activity of 5a is 200 times higher than that of compound 10.…”

Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors

“…Limiting conformational variants by constraints induced by formation of covalent bonds such as lactones, lactams, and disulfides, enhances their ability to interact with target receptors. Despite the benefits of incorporating cycles into peptides, few attempts have been made to cyclize biphalin's structure [9,[14][15][16][17]. In those cyclic biphalin studies, L-chirality of Cys and Pen residues at positions 2 and 2′ resulted in a significant loss in affinity and efficacy at the opioid receptors (OR), whereas Dchirality enhanced affinity and efficacy, similar to previous SAR studies on linear analogues [15,16].…”