Novel C-Terminus Modifications of the Dmt-Tic Motif:  A New Class of Dipeptide Analogues Showing Altered Pharmacological Profiles Toward the Opioid Receptors

Pagé, Daniel; Naismith, Angela; Schmidt, Ralf; Coupal, Martin; Labarre, Maryse; Gosselin, Mylène; Bellemare, Daniel; Payza, Kemal; Brown, W. A.

doi:10.1021/jm015532k

Cited by 24 publications

(42 citation statements)

References 30 publications

(24 reference statements)

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“…Then, the carboxylic group of 8 was reduced to hydroxyl with NaBH 4 [13]. The hydroxyl group of 9 was converted to azide 10 by a substitution reaction with NaN 3 [14].…”

Section: Resultsmentioning

confidence: 99%

From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease

et al. 2012

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Efforts to discover new drugs for Alzheimer’s disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1-42 induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1-42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer’s disease.

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“…Then, the carboxylic group of 8 was reduced to hydroxyl with NaBH 4 [13]. The hydroxyl group of 9 was converted to azide 10 by a substitution reaction with NaN 3 [14].…”

Section: Resultsmentioning

confidence: 99%

From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease

et al. 2012

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“…On the other hand, this phenomenon led to the development of more biologically stable structures with N‐terminal ( 7–9, 69 ) and Tic modifications ( 69 ) 46, 78–80. Nevertheless, even subtle modifications of N‐78 and C‐terminal substituents,56, 58, 63, 81–83 such as the removal of the carboxylate group45, 54, 84 or modification of the heteroaromatic structure of Tic,57, 62 profoundly altered the properties and activities of the Dmt–Tic peptides 55…”

Section: The Effect Of Dmt On Opioid Peptidesmentioning

confidence: 99%

“…This report will encompass only those bioactive compounds that have been developed since that time and exhibit K i values for the δ‐ or μ‐opioid receptors close to or less than 1 n M (Tables II and III). Analogues with inherently weak opioid receptor interactions or those published only with IC 50 values, in spite of their intrinsically high receptor activity56, 57 were not included in Tables II and III, although their functional bioactivities are found in Table IV ( 70–79 ). Furthermore, opioid analogues containing inactive Tyr58–61 or Phe cognates61 as well as 3′,5′‐diiodo‐ L ‐Tyr (Balboni et al, unpublished data), Dmt pseudopeptides lacking the heteroaromatic Tic nucleus,58 or a modified Tic aromatic ring,57, 62 C‐terminal extensions56, 58 or changes in chirality of the Dmt or Tic residues,63, 64 will not be discussed since they do not meet the defined criteria.…”

Section: Introductionmentioning

confidence: 99%

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

Cramer

Karam

Bothwell

et al. 2002

J of Comparative Neurology

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Nucleus magnocellularis (NM) in the avian auditory brainstem receives auditory input from nerve the VIIIth and projects bilaterally to nucleus laminaris (NL). This projection preserves binaural segregation in that ipsilateral NM projects to dorsal dendrites of NL and contralateral NM projects to ventral dendrites of NL. We have begun to examine the molecular signals that influence segregation of inputs onto discrete regions of NL cells. We previously showed that the Eph receptor, EphA4, is expressed selectively in the dorsal NL neuropil from embryonic day (E) 9 to E11, when NM axons grow into the NL neuropil. This asymmetric distribution suggests that EphA4 acts as a guidance molecule during binaural segregation. We report here on the developmental changes in the expression of two other Eph receptors, EphB2 and EphB5, and two ligands, ephrin-B1 and ephrin-B2, in the chick auditory brainstem. These proteins are expressed in the auditory nuclei during the maturation of the NM-NL projection. EphB2, EphB5, and ephrin-B1 are expressed in dorsal and ventral NL neuropil and at the midline of the brainstem at E10-E12. At this age, ephrin-B2, a ligand for EphB receptors and for EphA4, is expressed in NL cell bodies and NM-NL axons. The expression of these proteins diminishs in the posthatch ages examined. These results suggest that several members of the Eph family are involved in maturation of the nuclei and their projections. Moreover, ephrin-B2 in growing axons may interact with the asymmetrically expressed EphA4 during the establishment of binaural segregation.

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“…However, very small modifications such as going from an amide to a urea bond can change drastically the pharmacological profile. 10 Very few modifications of the Tic residue are allowed without loss of potency. 2,8,[11][12][13] Inversion of its chirality (D-Tic) resulted in a µ-selective agonist.…”

Section: Introductionmentioning

confidence: 99%

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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Novel C-Terminus Modifications of the Dmt-Tic Motif: A New Class of Dipeptide Analogues Showing Altered Pharmacological Profiles Toward the Opioid Receptors

Cited by 24 publications

References 30 publications

From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease

From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

A New Structural Motif for μ-Opioid Antagonists

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