680 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Letters
2, 3999-4002. (c) Michielin, O.; Zoete, V.; Gierasch, T. M.;
Eckstein, J .; Napper, A.; et al. Conformational Analysis of a
Stereochemically Complete Set of Cis-enediol Peptide Analogues.
J . Am. Chem. Soc. 2002, 124, 11131-11141.
were considerably lower than the EC50 value of 1
(31 ( 3 nM). These assays indicated that, like 2-4,
2,6-dimethyltyrosine analogues 5-10 are partial ago-
nists for MOR.
(4) Harrison, B. A.; Gierasch, T. M.; Neilan, C.; Pasternak, G. W.;
Verdine, G. L. High-Affinity µ Opioid Receptor Ligands Discov-
ered by the Screening of an Exhaustively Stereodiversified
Library of 1,5-Enediols. J . Am. Chem. Soc. 2002, 124, 13352-
13353.
(5) (a) Zadina, J . E.; Hackler, L.; Ge, L.-J .; Kastin, A. J . A Potent
and Selective Endogenous Agonist for the Mu-Opiate Receptor.
Nature 1997, 386, 499-502. (b) Zadina, J . E.; Martin-Schild, S.;
Gerall, A. A.; Kastin, A. J .; Hackler, L.; et al. Endomorphins:
Novel Endogenous Mu-Opiate Receptor Agonists in the Regions
of High Mu-Opiate Receptor Density. Ann. N. Y. Acad. Sci. 1999,
897, 136-144.
(6) Stereochemical labels for all compounds refer to the configura-
tion at C2, C3, C7, and C8, in that order, as labeled in compound
5.
Con clu sion s. Starting from structure 1 and using
both stereochemical and structural variation, we
have developed a new class of highly potent MOR
agonists. The 2,6-dimethyltyrosine analogues 5-10
showed improved affinity for MOR relative to the
tyrosine analogues 2-4. Stereochemical variation of
5 and 6 impacted the properties of these ligands less
than in 2; nevertheless, it enabled the discovery of
(S,R,S,R)-6, with unexpectedly high affinity and selec-
tivity, and (S,S,R,R)-5, with unexpectedly high efficacy.
While previous research has shown that isosteric re-
placements of amide bonds in 2,6-dimethyltyrosine
peptide ligands may eliminate MOR activity,9 our
diversity-based approach has discovered completely non-
peptidic, polyketide-like MOR partial agonists such as
(S,S,S,R)-9, with improved potency relative to 1 and
good selectivity and efficacy. These results suggest that
stereodiverse acyclic libraries will be useful for discover-
ing non-peptide ligands for multiple receptor types.
(7) Compounds (S,S,S,R)-2, 3, and 4 exhibited 71 ( 5%, 49 ( 4%,
and 75 ( 4% activation of MOR in GTP-γ-35S assays as described
in the footnote to Table 4.
(8) (a) Schiller, P. W.; Fundytus, M. E.; Merovitz, L.; Weltrowska,
G.; Nguyen, T. M.-D.; et al. The Opioid µ Agonist/µ Antagonist
DIPP-NH2[Ψ] Produces a Potent Analgesic Effect, No Physical
Dependence, and Less Tolerance than Morphine in Rats. J . Med.
Chem. 1999, 42, 3520-3526. (b) Schiller, P. W.; Nguyen, T. M.-
D.; Berezowska, I.; Dupuis, S.; Weltrowska, G.; et al. Synthesis
and in Vitro Opioid Activity Profiles of DALDA Analogues. Eur.
J . Med. Chem. 2000, 35, 895-901. (c) Hansen, D. W.; Stapelfeld,
A.; Savage, M. A.; Reichman, M.; Hammond, D. L.; et al.
Systematic Analgesic Activity and δ-Opioid Selectivity in [2,6-
dimethyl-Tyr1, D-Pen2, D-Pen5]enkephalin. J . Med. Chem. 1992,
35, 684-687. (d) Chandrakumar, N. S.; Stapelfeld, A.; Beardsley,
P. M.; Lopez, O. T.; Drury, B.; et al. Analogs of the δ Opioid
Receptor Selective Cyclic Peptide [cyclic][2-D-Penicillamine, 5-D-
penicillamine]-enkephalin: 2′,6′-Dimethyltyrosine and Gly3-
Phe4 Amide Bond Isostere Substitutions. J . Med. Chem. 1992,
35, 2928-2938. (e) Balboni, G.; Guerrini, R.; Salvadori, S.;
Bianchi, C.; Rizzi, D.; et al. Evaluation of the Dmt-Tic Pharma-
cophore: Conversion of a Potent δ-Opioid Receptor Antagonist
into a Potent δ Agonist and Ligands with Mixed Properties. J .
Med. Chem. 2002, 45, 713-720. (f) Salvadori, S.; Guerrini, R.;
Balboni, G.; Bianchi, C.; Bryant, S. D.; et al. Further Studies
on the Dmt-Tic Pharmacophore: Hydrophobic Substituents at
the C-Terminus Endow δ Antagonists To Manifest µ Agonism
or µ Antagonism. J . Med. Chem. 1999, 42, 5010-5019.
(9) (a) Chandrakumar, N. S.; Yonan, P. K.; Stapelfeld, A.; Savage,
M.; Rorbacher, E.; et al. Preparation and Opioid Activity of
Analogues of the Analgesic Dipeptide 2,6-Dimethyl-L-tyrosyl-
N-(3-phenylpropyl)-D-alaninamide. J . Med. Chem 1992, 35, 223-
233. (b) Pitzele, B. S.; Hamilton, R. W.; Kudla, K. D.; Tsymbalov,
S.; Stapelfeld, A.; et al. Enkephalin Analogs as Systemically
Active Antinociceptive Agents: O- and N-Alkylated Derivatives
of the Dipeptide Amide L-2,6-Dimethyltyrosyl-N-(3-phenylpro-
pyl)-D-alaninamide. J . Med. Chem. 1994, 37, 888-896.
(10) Adamson, J . G.; Blaskovich, M. A.; Groenevelt, H.; Lajoie, G. A.
Simple and Convenient Synthesis of tert-Butyl Ethers of Fmoc-
serine, Fmoc-threonine, and Fmoc-tyrosine. J . Org. Chem. 1991,
56, 3447-3449.
Ack n ow led gm en t. We thank Loriann Mahurter
and Claire Neilan for expert assistance. B.A.H. is the
recipient of a National Science Foundation predoctoral
fellowship. This work was supported by a gift from
Enanta Pharmaceuticals (to G.L.V.) and a grant from
NIH (to G.W.P.).
Su p p or t in g In for m a t ion Ava ila b le: Experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Harrison, Bryce A.
