Manuel Koller

Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice.

In metabotropic glutamate receptor 2 (mGlu(2)) knockout mice, the group 2 metabotropic glutamate receptor agonist LY314582 (20 mg/kg, i.p.), a racemate of LY354740, inhibits neither spontaneous nor phencyclidine (PCP)-induced (2.5 mg/kg, s.c.) locomotor activity. Since LY314582 attenuated spontaneous and PCP-induced locomotor activity in wild-type control mice, these data indicate that the effects of LY314582 are mediated via the mGlu(2) receptor and not via the mGlu(3) receptor.

Quinazolinedione sulfonamides: A novel class of competitive AMPA receptor antagonists with oral activity

Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models.

Novel N-methyl-d-aspartate receptor antagonists: a review of compounds patented since 2006

Importance of the field: The NMDA receptor is a complex ligand gated, voltage-dependent ion channel. It has been a drug target for > 25 years for neurological and psychiatric indications. Whereas the initial optimism to turn preclinically active compounds rapidly into drugs for human use was dampened, new insights into cellular receptor localization, role of subunits and receptor operation have kept the interest alive to modulate this receptor for therapeutic intervention. Areas covered in this review: The article describes the NMDA receptor antagonists patented since 2006. Also included are novel NMDA receptor ligands potentially useful for positron emission tomography imaging. What the reader will gain: The first section summarizes the current status of NMDA receptor pharmacology. This serves as a base for the next sections discussing the patented compounds with respect to their mode of action, potency and, in some cases, drugability. Take home message: The most important recent strategies aiming for inhibition of NMDA receptor-mediated neurotransmission avoid for safety reasons full receptor blockade but allow a low degree of normal receptor function. Approaches pursued by the latest patents comprise blocking the channel with compounds of low affinity, antagonizing receptor activity by highly potent NR2B ligands, partial agonism at the glutamate or glycine-binding site and improvement of pharmacokinetic properties of well established, safe antagonists by deuteration.

6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists.

A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage.

Drug Design, in Vitro Pharmacology, and Structure−Activity Relationships of 3-Acylamino-2-aminopropionic Acid Derivatives, a Novel Class of Partial Agonists at the Glycine Site on the N-Methyl-d-aspartate (NMDA) Receptor Complex

Retaining agonistic activity at the glycine coagonist site of the NMDA receptor in molecules derived from glycine or d-serine has proven to be difficult because in the vicinity of the alpha-amino acid group little substitution is tolerated. We have solved this problem by replacing the hydroxy group of d-serine with an amido group, thus keeping the hydrogen donor function and allowing for further substitution and exploration of the adjacent space. Heterocyclic substitutions resulted in a series of 3-acylamino-2-aminopropionic acid derivatives, with high affinities in a binding assay for the glycine site. In a functional assay assessing the activation of the glycine site, these compounds displayed a wide range of intrinsic efficacies, from antagonism to a high degree of partial agonism. Structure-activity relationships reveal that lipophilic substituents, presumably filling an additional hydrophobic pocket, are accepted by the glycine site, provided that they are separated from the alpha-amino acid group by a short linker.

Discovery of 1H-pyrrolo[2,3-c]pyridine-7-carboxamides as novel, allosteric mGluR5 antagonists.

1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency.

Inorganic iron complexes derived from the nitric oxide donor nitroprusside: competitive N-methyl-d-aspartate receptor antagonists with nanomolar affinity

Aquopentacyanoferrate(II), [Fe(II)H2O(CN)5]3-, is one of the photodegradation products of the vasodilator and nitric oxide donor nitroprusside. Earlier observations concerning the light dependence of N-methyl-D-aspartate (NMDA) receptor blockade by nitroprusside prompted us to examine the effects of this iron complex on the NMDA receptor. [Fe(II)H2O(CN)5]3- and two other related species, aminopentacyanoferrate(II) and aminopentacyanoferrate(III), were found to be highly potent, competitive, and selective NMDA receptor antagonists. In a binding assay for the transmitter recognition site on the NMDA receptor, these iron complexes displaced the radioligand [3H]CGP 39653 with nanomolar affinities. They did not displace radioligands labeling the channel ([3H]MK-801) or the glycine co-agonist ([3H]glycine) sites of the NMDA receptor, nor did they have any relevant affinities for a number of other neurotransmitter (alpha-adrenergic, 5-hydroxytryptamine, dopamine, opiate) receptors. The iron complexes blocked NMDA-induced depolarizations in rat cortical slices at submicromolar concentrations, whereas responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate were not affected. In another functional receptor assay (potentiation of [3H]MK-801 binding by glutamate under non-equilibrium conditions), Schild analysis demonstrated the competitive nature of the NMDA receptor antagonism. The pA2 values obtained from these experiments were similar to the pK(i) values derived from radioligand ([3H]CGP 39653) binding assays. To explain the high affinity and selectivity of these compounds for the NMDA receptor, a novel mechanism of antagonist-receptor interaction is proposed, involving a ligand exchange process in which a loosely bound species (here H2O or NH3) in the coordination sphere of the iron complex is replaced by a functional group of an amino acid side chain placed at the glutamate recognition site of the NMDA receptor, thereby hindering agonist binding.

Comparative pharmacology of the human NMDA-receptor subtypes R1-2A, R1-2B, R1-2C and R1-2D using an inducible expression system.

Pharmacological characterization of N-methyl-D-aspartate (NMDA) receptors has been hampered by the difficulty to outwit cytotoxicity after functional expression in recombinant systems. In this study a muristerone-inducible expression system for the NNMDA-R1 subunit was used. This was combined with constitutive expression of NMDA-R2A, 2B, 2C and 2D in different cell clones. After establishment of the cell lines, quantitative RT-PCR demonstrated the inducibility of the NNMDA-R1 subunit, and verified the expression of the NMDA-R2 subunits in the different cell clones. Functional responses were characterized using calcium influx through the ion channel as a robust assay system. Stimulation of the NMDA-receptor subtypes in the different cell lines led to calcium transients which were rising gradually, peaked after 30-160 s and declined thereafter very slowly. The expression of the four different NMDA-receptor subtypes in the same cellular background allowed a direct pharmacological comparison of the different receptors. Glutamate showed the highest potency at the NMDA-R1-2D. NMDA displayed at all subtypes a lower potency compared to glutamate and was a partial agonist except at the NMDA-R1-2D. 20 antagonists were tested in this study and the pharmacological characterization of the inhibition of glutamate-evoked elevation of intracellular free Ca(2+) revealed a distinct rank order of antagonist potency for each receptor subtype. These data illustrate that assessment of calcium transients upon receptor stimulation in the same cellular background is a powerful tool to compare the functional effects of compounds acting at the different NMDA-R2 receptors.

Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist

A series of potent quinazolinedione sulfonamide antagonists of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor were designed and synthesized. The structure–activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N‐[7‐isopropyl‐6‐(2‐methylpyrazol‐3‐yl)‐2,4‐dioxo‐1H‐quinazolin‐3‐yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)‐induced generalized tonic–clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X‐ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.