Ivar M. McDonald

Effect of alpha7 nicotinic acetylcholine receptor agonists on attentional set-shifting impairment in rats

RationaleAttentional set shifting, a measure of executive function, is impaired in schizophrenia patients. Current standard of care has little therapeutic benefit for treating cognitive dysfunction in schizophrenia; therefore, novel drugs and animal models for testing novel therapies are needed. The NMDA receptor antagonist, MK-801, produces deficits in a rat maze-based set-shifting paradigm, an effect which parallels deficits observed on tests of executive function in schizophrenia patients. Alpha7 nicotinic acetylcholine receptor (nAChR) agonists, currently under clinical development by several companies, show promise in treating cognitive symptoms in schizophrenia patients and can improve cognition in various animal models.ObjectivesThe objectives of the present study were to determine whether the MK-801 deficit in set shifting could be reproduced in a drug discovery setting and to determine whether cognitive improvement could be detected for the first time in this task with alpha7 nAChR agonists.ResultsThe data presented here replicate findings that a systemic injection of the NMDA receptor antagonist MK-801 can induce a deficit in set shifting in rats. Furthermore, the deficit could be reversed by the atypical antipsychotic clozapine as well as by several alpha7 nAch receptor agonists (SSR-180711, PNU-282987, GTS-21) with varying in vitro properties.ConclusionsResults indicate that the MK-801 set-shift assay is a useful preclinical tool for measuring prefrontal cortical function in rodents and can be used to identify novel mechanisms for the potential treatment of cognitive deficits in schizophrenia.

Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists

High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit (1) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high pKa. A novel 4-fluoroquinuclidine significantly lowered the pKa of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay.

General Method for the Preparation of Electron-Deficient Imidazo[1,2-a]pyridines and Related Heterocycles

A new annulation method for the preparation of the imidazo[1,2-a]pyridine ring system under mild conditions is presented. Treatment of a 2-aminopyridine with a dimethylketal tosylate in acetonitrile at elevated temperature (80-140 °C) in the presence of catalytic Sc(OTf)3 provides the imidazo[1,2-a]pyridine product in good yield. The annulation method is broadly applicable to electron-poor 2-aminopyridines and displays a complementary profile to the classic preparation of the imidazo[1,2-a]pyridine ring system by reaction of a bromoketone with electron-rich and -neutral substrates. The scope of the process and mechanistic considerations are discussed.

Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents.

Abstract The &agr;7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS‐902483, a selective potent &agr;7 nicotinic acetylcholine receptor partial agonist, in relationship to &agr;7 nicotinic acetylcholine receptor occupancy. BMS‐902483 has low nanomolar affinity for rat and human &agr;7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat &agr;7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS‐902483 improved 24 h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1 mg/kg and reversed MK‐801‐induced deficits in a rat attentional set‐shifting model of executive function with an MED of 3 mg/kg. Enhancement of novel object recognition was blocked by the silent &agr;7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS‐902483 was mediated by &agr;7 nicotinic acetylcholine receptors. BMS‐902483 also reversed ketamine‐induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long‐term potentiation examined 24 h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that &agr;7 receptor occupancy ranged from 64% (novel object recognition) to ˜90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS‐902483.

BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia

The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.

Unlocking P(V): Reagents for chiral phosphorothioate synthesis

A swift citrusy path to chiral phosphorus The phosphates in the backbones of DNA and RNA are often drawn like crosses but are in fact tetrahedral. Sulfur is sometimes substituted for one of the phosphate oxygens during development of nucleotide-based drugs. Because of the geometry, this swap can lead to two different isomers. Knouse et al. report a pair of phosphorus reagents that conveniently produce either isomer selectively. This ability depended on the configuration of appended limonene substituents that are subsequently jettisoned. In addition to simplifying the route to sulfur-substituted oligonucleotides, these reagents will enable more precise studies of each isomers distinct bioactivity. Science, this issue p. 1234 Limonene-substituted phosphorus reagents offer a simplified and stereoselective route to nucleotide-based drug candidates. Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]–based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

B-973, a novel piperazine positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Abstract The alpha7 (&agr;7) nicotinic acetylcholine receptor is a therapeutic target for cognitive disorders. Here we describe 3‐(3,4‐difluorophenyl)‐N‐(1‐(6‐(4‐(pyridin‐2‐yl)piperazin‐1‐yl)pyrazin‐2‐yl)ethyl)propanamide (B‐973), a novel piperazine‐containing molecule that acts as a positive allosteric modulator of the &agr;7 receptor. We characterize the action of B‐973 on the &agr;7 receptor using electrophysiology and radioligand binding. At 0.1 mM acetylcholine, 1 &mgr;M B‐973 potentiated peak acetylcholine‐induced currents 6‐fold relative to maximal acetylcholine (3 mM) and slowed channel desensitization, resulting in a 6900‐fold increase in charge transfer. The EC50 of B‐973 was approximately 0.3 &mgr;M at acetylcholine concentrations ranging from 0.03 to 3 mM. At a concentration of 1 &mgr;M, B‐973 shifted the acetylcholine EC50 of peak currents from 0.30 mM in control to 0.007 mM. B‐973 slowed channel deactivation upon acetylcholine removal (&tgr;=50 s) and increased the affinity of the &agr;7 agonist [3H]A‐585539. In the absence of exogenously added acetylcholine, application of B‐973 at concentrations >1 &mgr;M induced large methyllycaconitine‐sensitive currents, suggesting B‐973 can function as an Ago‐PAM at high concentrations. B‐973 will be a useful probe for investigating the biological consequences of increasing &agr;7 receptor activity through allosteric modulation. Graphical abstract Figure. No caption available.