Rikke Bergmann

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We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and(More)
A new field-derived 3D method for receptor-based scaffold hopping, implemented in the software SHOP, is presented. Information from a protein-ligand complex is utilized to substitute a fragment of the ligand with another fragment from a database of synthetically accessible scaffolds. A GRID-based interaction profile of the receptor and geometrical(More)
A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABA(A)R binding affinities to native GABA(A) receptors (K(i) 1.1-24 μM). The(More)
A new GRID-based method for scaffold hopping (SHOP) is presented. In a fully automatic manner, scaffolds were identified in a database based on three types of 3D-descriptors. SHOP's ability to recover scaffolds was assessed and validated by searching a database spiked with fragments of known ligands of three different protein targets relevant for drug(More)
A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA(A) receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. The unsubstituted 4-AHP analogue (2a) (EC(50) 19 μM, R(max) 69%) was a moderately potent agonist at human α(1)β(2)γ(2) GABA(A)(More)
The ionotropic GABAA receptors (GABAARs) are widely distributed in the central nervous system where they play essential roles in numerous physiological and pathological processes. A high degree of structural heterogeneity of the GABAAR has been revealed and extensive effort has been made to develop selective and potent GABAAR agonists. This review(More)
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