A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 mu mol/kg compared to control. (C) 2018 Elsevier Ltd. All rights reserved.

Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (sc 60mg/kg).

A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 mu M), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration. (c) 2010 Elsevier Ltd. All rights reserved.

Note: The version number of CRATE is 9.0.1. This means that CRATE–version 9.0.1 is based on POLYRATE–version 9.0. The interface of CHARMM–versions c28b1 to c28b2 with POLYRATE–version 9.0 will result in CHARMMRATE–1.0, whereas the interface of CHARMM–version c28b3 and later with POLYRATE–version 9.0 gives CHARMMRATE–2.0. CRATE abstract CRATE is a package supporting the CHARMMRATE module of CHARMM. This package contains (1) a utility to prepare POLYRATE for use with the CHARMMRATE module of CHARMM, (2) test runs for enzyme kinetics simulations with CHARMMRATE, and (3) additional background information related to CRATE and CHARMMRATE. The standard POLYRATE program requires modifications to make it compatible with CHARMM. The modifications are made to enable efficient transfer of information between CHARMM and POLYRATE and to eliminate conflicts and other problems during complication. This package contains the modifications to be made. and polysz.src are modified by a script called install_cr.com that is provided as part of the CRATE utility. In particular, subroutine names are modified to remove conflicts with the CHARMM libraries, an additional keyword is added to the input read options in subroutine read5, some statements are commented out because they call ACES routines that are not part of POLYRATE, some subroutines are commented because they will never be used, all tab characters are removed to allow the CHARMM preprocessor to process the code properly, and all source code files are given the extension required by CHARMM. The subroutine dattim.f90 is copied from the polyrate/util/ directory by the script install_cr.com in order to substitute the machine-dependent subroutine. In addition, the CRATE utility contains (i) a subroutine called " maino, " which replaces the POLYRATE main routine, (ii) a new set of " hooks " (interface subprograms) that are required to interface CHARMM with POLYRATE, (iii) a version of the POLYRATE param.inc file that has dimensions large enough to run the CHARMMRATE test run, and iv) three source files, fdiag.f, pmf_projct.f, and charmmrate.inc. The first file is a POLYRATE subroutine that has been modified, and the last two are new source files. They contain the additional code necessary to carry out projected instantaneous normal mode analysis. The Page 3 of 20 CRATE package contains information about the changes to be made by the user to perform this kind of calculation. The CRATE package also contains two test runs for xylose isomerase. The first of these test runs reads in the coordinates for 4 configurations of …

We report a calculation for a trideuteration kinetic isotope effect (KIE) for the proton transfer step in the oxidation of methylamine by the quinoprotein methylamine dehydrogenase (MADH). The potential field includes 11 025 atoms, and the dynamics are based on a quantum mechanical/molecular mechanical (QM/MM) dynamics simulation and ensemble-averaged canonical variational transition state theory with small-curvature multidimensional tunneling contributions. About 1% of the reaction occurs by overbarrier processes, with the rest due to tunneling. We compute a KIE of 18.3, in good accord with experiment (17.2), but the calculated KIE is reduced to 5.9 when we omit tunneling. This provides the most striking evidence yet for the contribution of tunneling processes to enzymatic reactions at physiological temperatures.

We present an overview of new procedures for including quantum mechanical effects in enzyme kinetics. Quantum effects are included in three ways: (1) The electronic structure of the atoms in the catalytic center is treated quantum mechanically in order to calculate a realistic potential energy surface for the bond rearrangement process. (2) The discrete nature of quantum mechanical vibrational energies is incorporated in the treatment of nuclear motion for computing the potential of mean force. (3) Multidimensional tunneling contributions are included. These procedures are illustrated by applications to proton abstractions catalyzed by enolase and methylamine dehydrogenase and hydride-transfer reactions by alcohol dehydrogenase and xylose isomerase.

Hybrid quantum mechanical (QM) and molecular mechanical (MM) potentials are becoming increasingly important for studying condensed-phase systems but one of the outstanding problems in the field has been how to treat covalent bonds between atoms of the QM and MM regions. Recently, we presented a generalized hybrid orbital (GHO) method that was designed to tackle this problem for hybrid potentials using semiempirical QM methods [Gao et al. (1998) J Phys Chem A 102: 4714–4721]. We tested the method on some small molecules and showed that it performed well when compared to the purely QM or MM potentials. In this article, we describe the formalism for the determination of the GHO energy derivatives and then present the results of more tests aimed at validating the model. These tests, involving the calculation of the proton affinities of some model compounds and a molecular dynamics simulation of a protein, indicate that the GHO method will prove useful for the application of hybrid potentials to solution-phase macromolecular systems.