TY - JOUR
T1 - Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors
AU - Yakoub, Kirsten
AU - Jung, Sascha
AU - Sattler, Christian
AU - Damerow, Helen
AU - Weber, Judith
AU - Kretzschmann, Annika
AU - Cankaya, Aylin S
AU - Piel, Markus
AU - Rösch, Frank
AU - Haugaard, Anne S
AU - Frølund, Bente
AU - Schirmeister, Tanja
AU - Lüddens, Hartmut
PY - 2018/3/8
Y1 - 2018/3/8
N2 - δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.
AB - δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.
KW - GABA-A Receptor Antagonists/chemistry
KW - Humans
KW - Imidazoles/chemistry
KW - Inhibitory Concentration 50
KW - Protein Subunits/metabolism
KW - Pyridines/chemistry
KW - Receptors, GABA-A/metabolism
KW - Structure-Activity Relationship
U2 - 10.1021/acs.jmedchem.7b01484
DO - 10.1021/acs.jmedchem.7b01484
M3 - Journal article
C2 - 29451785
SN - 0022-2623
VL - 61
SP - 1951
EP - 1968
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -