Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

Abstract

The interaction of diazepine analogues like clozapine or olanzapine with D2 receptor was greatly affected by a mixture of HRP/H(2)O(2) known to induce the formation of nitrenium ion. Unlike diazepine derivatives, the oxidative mixture had low impact on the affinity of oxa- and thiazepine derivatives such as loxapine, clothiapine or JL13 for the D2 receptor. Molecular docking simulations revealed a huge difference between the mode of interaction of clozapine nitrenium ion and the parent drug. Electronic and geometric changes of the tricyclic ring system caused by the oxidation appeared to prevent the compound finding the correct binding mode and could therefore explain the difference observed in binding affinities.

Identification and pharmacological characterization of succinate receptor agonists

“…First, the human sequence of the succinate receptor obtained from the Universal Protein Resource (code entry: Q9BXA5) were aligned with the sequence of another GPCR, the human β 2 adrenoceptor (code entry P07550) by using the FUGUE module (Shi et al , ). The next step was the copy of a set of constraints derived from the crystal structure of the human β 2 adrenoceptor to the corresponding residues of the sequences to be modelled using the ORCHESTRAR protein structure modelling module (Dilly and Liegeois, ). As succinate is an agonist at succinate receptors, the receptor model was built in its active form from a crystal structure of the activated turkey β 2 adrenoceptor (PDB code 3P0G) (Rasmussen et al , ).…”

The 5-HT1A Agonism Potential of Substituted Piperazine-Ethyl-Amide Derivatives Is Conserved in the Hexyl Homologues: Molecular Modeling and Pharmacological Evaluation

“…The second step consisted in the transfer of a set of constraints derived from the ligand-biased crystal structure of the turkey β1 adrenergic GPCR (PDB entry ) to the corresponding amino acids of the sequence to be modeled using the ORCHESTRAR protein structure modeling module . Indeed, in the model-building protocol, the cocrystallized agonist isoprenaline in the β1 crystal structure was replaced by R-8-OH-DPAT, a full and potent agonist of the 5-HT 1A receptor (Figure ). , For this purpose, a complete coverage of conformational space (308 conformations) for R-8-OH-DPAT was generated using the program Random Search of SYBYL.…”

Structural Insights into 5-HT1A/D4 Selectivity of WAY-100635 Analogues: Molecular Modeling, Synthesis, and in Vitro Binding

“…The next step was the copy of a set of constraints derived from ligand-biased crystal structures of the turkey β1 adrenergic GPCR to the corresponding residues of the sequences to be modeled using the ORCHESTRAR protein structure modeling module. 21 Since the compounds are 5-HT 1A antagonists, 12 the 5-HT 1A receptor model was built in its inactive form from a crystal structure of the inactivated turkey β1 adrenergic receptor (PDB code 2VT4). 22 In the modeling protocol, the cocrystallized antagonist cyanopindolol in the inactivated β1 crystal structure was replaced by WAY-100635.…”