New scaffolds in the development of Mu opioid-receptor ligands

Pagé, Daniel; Nguyen, Natalie; Bernard, Sylvain; Coupal, Martin; Gosselin, Mylène; Lepage, Julie; Adam, Lynda; Brown, W. A.

doi:10.1016/s0960-894x(03)00194-x

Cited by 11 publications

(6 citation statements)

References 19 publications

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“…On the basis of structural features of the Dmt-Tic pharmacophore, we have identified a new structural motif leading to a fairly potent μ-opioid antagonist. Similar structural considerations have led Pagé et al to another new scaffold for μ-opioid ligands in which the Tic residue is still present . In the stuctural motif described here, all stereoisomers of 5 are interacting more effectively with the μ-opioid receptor than with the δ-opioid receptor (Tables and ).…”

Section: Discussionsupporting

confidence: 61%

A New Structural Motif for μ-Opioid Antagonists

et al. 2005

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On the basis of the structural features of the Dmt-Tic pharmacophore, a new motif leading to a fairly potent mu-opioid antagonist is described. This motif contains the 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-one skeleton as a substitute for the Tic residue, which provides the conformational constraint compatible with the mu-opioid receptor. The stereoselective synthesis of four stereoisomers is performed starting from homochiral 2',6'-dimethyltyrosine (Dmt) and o-aminomethylphenylalanine.

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Section: Discussionsupporting

confidence: 61%

A New Structural Motif for μ-Opioid Antagonists

et al. 2005

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“…13 From these and other studies, it was concluded that small, discrete, and subtle modifications can drastically change the pharmacological profile in molecules related to the Dmt-Tic pharmacophore. [15][16][17]…”

Section: Introductionmentioning

confidence: 99%

Effect of Lysine at C-Terminus of the Dmt-Tic Opioid Pharmacophore

Balboni¹,

Congiu²,

Zotti³

et al. 2006

J. Med. Chem.

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Substitution of Gly with side-chain-protected or unprotected Lys in lead compounds containing the opioid pharmacophore Dmt-Tic [H-Dmt-Tic-Gly-NH-CH(2)-Ph, mu agonist/delta antagonist; H-Dmt-Tic-Gly-NH-Ph, mu agonist/delta agonist; and H-Dmt-Tic-NH-CH(2)-Bid, delta agonist (Bid = 1H-benzimidazole-2-yl)] yielded a new series of compounds endowed with distinct pharmacological activities. Compounds (1-10) included high delta- (Ki(delta) = 0.068-0.64 nM) and mu-opioid affinities (Ki(mu) = 0.13-5.50 nM), with a bioactivity that ranged from mu-opioid agonism {10, H-Dmt-Tic-NH-CH[(CH2)4-NH2]-Bid (IC50 GPI = 39.7 nM)} to a selective mu-opioid antagonist [3, H-Dmt-Tic-Lys-NH-CH2-Ph (pA2(mu) = 7.96)] and a selective delta-opioid antagonist [5, H-Dmt-Tic-Lys(Ac)-NH-Ph (pA2(delta) = 12.0)]. The presence of a Lys linker provides new lead compounds in the formation of opioid peptidomimetics containing the Dmt-Tic pharmacophore with distinct agonist and/or antagonist properties.

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“…The synthesis of µ-opioid receptor antagonist libraries has been reported by the AstraZeneca group [56]. The target compounds were based on functionalized tetrahydroisoquinolines for which the most potent derivative disclosed was (10).…”

Section: Chemokine Receptorsmentioning

confidence: 99%

“…Lastly, computational programs were utilized in library design to identify compounds that displayed an optimal interaction with the altered amino acid residues. Compounds with excellent selectivity, (56), were subsequently discovered. (Fig.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

Shuttleworth¹,

Connors²,

Fu³

et al. 2005

CMC

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This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.

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New scaffolds in the development of Mu opioid-receptor ligands

Cited by 11 publications

References 19 publications

A New Structural Motif for μ-Opioid Antagonists

A New Structural Motif for μ-Opioid Antagonists

Effect of Lysine at C-Terminus of the Dmt-Tic Opioid Pharmacophore

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

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