2016
DOI: 10.1016/j.ejmech.2015.11.001
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Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies

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Cited by 10 publications
(9 citation statements)
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“…Besides the core structure, the effective pharmacophore linkers at position 3 of the quinuclidine scaffold are ether, carbamate, urea, amide, sulfonamide, oxazole, oxadiazole, and triazole. , Another approach in the design of α7 ligands was the synthesis of conformational restricted analogues such as oxazolidinone AR-R17779 . Among them, the compounds containing the quinuclidine anti -1,2,3-triazole skeleton bind with high affinity and selectivity to the α7 nAChR . This hydrophobic motif in particular plays an important role in receptor subtype recognition through the interaction with amino acid residues of the complementary face, which has been demonstrated as an essential part for ligand selectivity among various nAChR subtypes. We recently reported three series of novel potent and selective α7 nAChR agonists featuring the quinuclidine anti -1,2,3-triazole containing molecules ( IND8 and QND8 ) that demonstrated cognitive enhancement in mice .…”
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confidence: 99%
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“…Besides the core structure, the effective pharmacophore linkers at position 3 of the quinuclidine scaffold are ether, carbamate, urea, amide, sulfonamide, oxazole, oxadiazole, and triazole. , Another approach in the design of α7 ligands was the synthesis of conformational restricted analogues such as oxazolidinone AR-R17779 . Among them, the compounds containing the quinuclidine anti -1,2,3-triazole skeleton bind with high affinity and selectivity to the α7 nAChR . This hydrophobic motif in particular plays an important role in receptor subtype recognition through the interaction with amino acid residues of the complementary face, which has been demonstrated as an essential part for ligand selectivity among various nAChR subtypes. We recently reported three series of novel potent and selective α7 nAChR agonists featuring the quinuclidine anti -1,2,3-triazole containing molecules ( IND8 and QND8 ) that demonstrated cognitive enhancement in mice .…”
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confidence: 99%
“…Quinuclidine-containing compounds are well recognized for nAChR interaction and the selectivity of their ( R )-enantiomers for α7 nAChR. However, detailed information with regard to their ( S )-enantiomers was missing at the beginning of this study. , Thus, both enantiomers were prepared to investigate the influence of chirality on the selectivity as well as the affinity for nAChR. Second, the orientation of the hydrophobic aromatic ring was explored by altering the substitution from para to meta .…”
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confidence: 99%
“…To identify fluorescent α 7 nAChR agonists, we envisioned to survey bicyclic tertiary amines known as selective α 7 nAChR agonists, in particular focusing on PNU‐282,987, EVP‐6124, RG3487, PHA‐543613, or PHA‐568487 . These compounds are derived from ( R )‐ or ( S )‐3‐amino‐quinuclidine featuring the essential agonist pharmacophore comprising an ammonium group participating in a cation– π interaction and an aromatic group participating in a π – π interaction in the hydrophobic binding pocket ( Fig.…”
Section: Introductionmentioning
confidence: 99%
“…1,2,3-Triazoles have received attention in medicinal chemistry and organic chemistry due to their excellent biological activities and easy synthesis via click reactions. 1,2 In recent years, 1,2,3-triazoles have gained special attention as antiproliferative agents because several biologically active compounds contain that group such as the spirooxindole-derived morpholine-fused-1,2,3-triazole 1, 3 and the 1,2,3-triazole linked chalcone 2 (Fig. 1).…”
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confidence: 99%
“…thio]methyl}-1H-1,2,3triazol-1-yl)propoxy]phenyl}-1-(4-fluorophenyl)prop-2-en-1-one (III-1): Yellow solid; yield 85%; m.p. 129-131 °C;1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (dd, J = 8.8, 5.5 Hz, 2H), 7.79 (d, J = 15.6 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.54 (s, 1H), 7.40 (d, J = 15.6 Hz, 1H), 7.18 (t, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 6.7 Hz, 2H), 4.41 (s, 2H), 4.14 (t, J = 8.0 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.36 (t, J = 8.0 Hz, 2H), 2.54-2.31 (m, 2H);13 C NMR (100 MHz, CDCl 3 ) δ 188.8, 166.8, 164.8, 164.3, 160.5, 144.6, 134.8, 131.1, 130.3, 127.9, 123.2, 119.5, 115.6, 114.9, 64.2, 64.1, 47.0, 35.8, 29.8, 27.1; HRMS (ESI) calcd for C 24 H 23 FN 4 NaO 2 S 2 [M + Na] + : 505.1148, found: 505.1144. (E) -1-(4-chlorophenyl) -3-{4-[3-(4-{[(4,5-dihydrothiazol-2-yl) thio]methyl}-1H-1,2,3-triazol-1-yl) propoxy]phenyl}prop-2-en-1-one (III-2): Yellow solid; yield 62%; m.p.…”
mentioning
confidence: 99%