Cyclic morphiceptin analogs: cyclization studies and opioid activities in vitro

Abstract

Attempts were undertaken to develop cyclic β‐casomorphin‐5 analogs with improved opioid activity profiles by deletion of the glycine residue in position 5, leading to analogs structurally related to the opioid peptide morphiceptin (H‐Tyr‐Pro‐Phe‐Pro‐NH2). The tetrapeptide sequence Boc‐Tyr(tBu)‐D‐Xaa‐Phe‐Yaa‐OH (Xaa = Lys, Orn, A2bu; Yaa = Pro in L‐ or D‐configuration) was used to study the influence of ring size and chirality on the yield of cyclization between the ω‐amino group of Xaa and the C‐terminal carboxyl group. In all cases the cyclization reaction was performed under identical experimental conditions to allow a direct comparison with regard to yield and homogeneity. The reaction products were purified by crystallization and liquid chromatography, and were characterized by HPLC, TLC, electrospray mass spectrometry and 1H‐NMR spectroscopy. In none of the reactions performed with the cyclization precursors containing proline in the L‐configuration could a cyclic monomer be detected, and the cyclodimer (7–9) was the exclusive product in each case. Cyclodimerization was also the favored reaction in the attempted formation of the 11‐membered ring of the cyclic [D‐A2bu2, D‐Pro4]‐morphiceptin analog 12, since only traces of the monomer were found. In the case of both the [D‐Lys2, D‐Pro4]‐analog 10 and the [D‐Orn2, D‐Pro4]‐ analog 11, the cyclomonomer/cyclodimer ratio was about 80: 20. The cyclic monomers 10 and 11 showed high opioid activity in the μ‐receptor‐representative guinea pig ileum assay (IC50= 2–5 nM) and in the δ‐receptor representative mouse vas deferens assay (IC50= 50–60 nM), whereas the potency of the cyclodimers was 2–3 orders of magnitude lower in both in vitro bioassays.

Redoubling the ring size of an endomorphin‐2 analog transforms a centrally acting mu‐opioid receptor agonist into a pure peripheral analgesic

“…Among various synthetic approaches, cyclization of peptides is a strategy often used to achieve increased bioavailability and therefore improved pharmacological properties. The first cyclic opioid peptide analogs were synthesized already in the 1980s and the formation of cyclodimers was observed by several authors …”

Solid-phase peptide head-to-side chain cyclodimerization: Discovery of C2-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors

“…Although several peptide natural products, such as gramicidin S[27] and marine cyclodepsipeptide IB-01212[19], are known to possess C 2 -symmetry, there are few examples of peptide cyclodimerizations pertinent to development of peptides with enhanced biological activities, which include syntheses of cyclic biphalin[70] and morphiceptin[96] analogues. Thus, practical aspects of this area of peptide chemistry and its applications to development of novel GPCR ligands remain relatively unexplored.…”