Gmeiner P

References (3)

Title : Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo - Scheiner_2019_J.Med.Chem_62_9078
Author(s) : Scheiner M , Dolles D , Gunesch S , Hoffmann M , Nabissi M , Marinelli O , Naldi M , Bartolini M , Petralla S , Poeta E , Monti B , Falkeis C , Vieth M , Hubner H , Gmeiner P , Maitra R , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 62 :9078 , 2019
Abstract : We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of beta-amyloid (Abeta), and Abeta self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).
ESTHER : Scheiner_2019_J.Med.Chem_62_9078
PubMedSearch : Scheiner_2019_J.Med.Chem_62_9078
PubMedID: 31609608

Title : Activation and allosteric modulation of a muscarinic acetylcholine receptor - Kruse_2013_Nature_504_101
Author(s) : Kruse AC , Ring AM , Manglik A , Hu J , Hu K , Eitel K , Hubner H , Pardon E , Valant C , Sexton PM , Christopoulos A , Felder CC , Gmeiner P , Steyaert J , Weis WI , Garcia KC , Wess J , Kobilka BK
Ref : Nature , 504 :101 , 2013
Abstract : Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the beta2 adrenergic receptor (beta2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the beta2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.
ESTHER : Kruse_2013_Nature_504_101
PubMedSearch : Kruse_2013_Nature_504_101
PubMedID: 24256733

Title : Muscarinic receptors as model targets and antitargets for structure-based ligand discovery - Kruse_2013_Mol.Pharmacol_84_528
Author(s) : Kruse AC , Weiss DR , Rossi M , Hu J , Hu K , Eitel K , Gmeiner P , Wess J , Kobilka BK , Shoichet BK
Ref : Molecular Pharmacology , 84 :528 , 2013
Abstract : G protein-coupled receptors (GPCRs) regulate virtually all aspects of human physiology and represent an important class of therapeutic drug targets. Many GPCR-targeted drugs resemble endogenous agonists, often resulting in poor selectivity among receptor subtypes and restricted pharmacologic profiles. The muscarinic acetylcholine receptor family exemplifies these problems; thousands of ligands are known, but few are receptor subtype-selective and nearly all are cationic in nature. Using structure-based docking against the M2 and M3 muscarinic receptors, we screened 3.1 million molecules for ligands with new physical properties, chemotypes, and receptor subtype selectivities. Of 19 docking-prioritized molecules tested against the M2 subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar Ki values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M2 and M3 receptors, we selected molecules predicted by docking to bind to the M3 and but not the M2 receptor. Of 16 molecules tested, 8 bound to the M3 receptor. Whereas selectivity remained modest for most of these, one was a partial agonist at the M3 receptor without measurable M2 agonism. Consistent with this activity, this compound stimulated insulin release from a mouse beta-cell line. These results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology.
ESTHER : Kruse_2013_Mol.Pharmacol_84_528
PubMedSearch : Kruse_2013_Mol.Pharmacol_84_528
PubMedID: 23887926