I have a feeling there are some "hidden gems" in the recent opioid peptide literature detailing analogs, or important information pertaining to making other analogs, that could allow one to have knowledge of a sequence and subsequent peptide that could be of recreational use.
Something like this:
Chem Biol Drug Des. 2009 Aug 20.
Cyclic Opioid Peptide Agonists and Antagonists Obtained Via Ring-Closing Metathesis.
Berezowska I, Lemieux C, Chung NN, Wilkes BC, Schiller PW.
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC, Canada H2W 1R7.
The opioid peptide H-Tyr-c[D-Cys-Phe-Phe-Cys]NH(2) cyclized via a methylene dithiother is a potent and selective mu opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2'6'-dimethyltyrosine (Dmt), 3-[2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in the 1-position were prepared. The peptides were synthesized on solid-phase by substituting d-allylglycine and (2S)-2-amino-5-hexenoic acid in position 2 and 5, respectively, followed by ring-closing metathesis. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated -CH(2)-CH(2)- bridged peptides. All six Tyr(1)- and Dmt(1)-dicarba analogues retained high mu and delta opioid agonist potency and showed only slight or no preference for mu over delta receptors. As expected, the six Dhp(1)- and (2S)-Mdp(1)-dicarba analogues turned out to be mu opioid antagonists but, surprisingly, displayed a range of different efficacies (agonism, partial agonism or antagonism) at the delta receptor. The obtained results indicate that the mu versus delta receptor selectivity and the efficacy at the delta receptor of these cyclic peptides depend on distinct conformational characteristics of the 15-membered peptide ring structure, which may affect the spatial positioning of the exocyclic residue and of the Phe(3) and Phe(4) side chains.
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J Med Chem. 2007 Jun 28;50(13):3138-42.
Synthesis of stable and potent delta/mu opioid peptides: analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis.
Mollica A, Guardiani G, Davis P, Ma SW, Porreca F, Lai J, Mannina L, Sobolev AP, Hruby VJ.
Università degli Studi G. D' Annunzio, Via dei Vestini 31, I-66013 Chieti, Italy.
Ring-closing metathesis has emerged as a powerful tool in organic synthesis for generating cyclic structures via C-C double bond formation. Recently, it has been successfully used in peptide chemistry for obtaining cyclic molecules bridged through an olefin unit in place of the usual disulfide bond. Here, we describe this approach for obtaining cyclic olefin bridged analogues of H-Tyr-c[D-Cys-Gly-Phe-Cys]-OH. The synthesis of the new ligands was performed using the second generation Grubbs' catalyst. The resulting cis-8 (cDADAE) and trans-9 (tDADAE) were fully characterized and tested at delta, mu, and kappa opioid receptors. Also the linear precursor 13 (lDADAE) and the hydrogenated derivative 11 (rDADAE) also were tested. All the cyclic products containing a olefinic bond are slightly selective but highly active and potent for the delta and mu opioid receptors. Activity toward the kappa opioid receptors was absent or very low.
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J Med Chem. 2007 Jun 14;50(12):2779-86.
Design, synthesis, and biological evaluation of novel bifunctional C-terminal-modified peptides for delta/mu opioid receptor agonists and neurokinin-1 receptor antagonists.[b/]
Yamamoto T, Nair P, Davis P, Ma SW, Navratilova E, Moye S, Tumati S, Lai J, Vanderah TW, Yamamura HI, Porreca F, Hruby VJ.
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
A series of bifunctional peptides that act as agonists for delta and mu opioid receptors with delta selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at delta/mu opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3) 2 (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)2 (7) had excellent agonist activity for both delta opioid and mu opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.
-------->>> With regards to this last paper I saw a talk about this recently with a lot of in vivo data from mouse models and expect them to be doing some preclinical trials now or in the near future as the guy made it out to look like he had a "near ideal" pain-relieving compound that had no sign of behavioral effects or withdrawal/addiction. It almost sounded too good to be true. His explanation was in the fact that it had activity and the opioid receptor simultaneously with the NK1 antagonism, but that they couldn't fully prove it yet or something. Either way more information is bound to come up sooner or later.