ABSTRACT
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Alkylation , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Drug Design , Humans , Receptor, Serotonin, 5-HT2A/drug effects , Receptor, Serotonin, 5-HT2C/drug effects , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Serotonin/drug effects , Recombinant Proteins/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)(2) receptor and specifically on the 5-HT(2):dopamine D(2) affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT(2A) and 5-HT(2C) receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT(1A) receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT(1A) receptor as well as is its claimed partial agonist activity at the dopamine D(2) receptor.
Subject(s)
Antipsychotic Agents/pharmacology , Biogenic Monoamines/metabolism , Receptors, Dopamine/drug effects , Receptors, Serotonin/drug effects , Schizophrenia/drug therapy , Schizophrenia/metabolism , Animals , Benzodiazepines/pharmacology , Binding, Competitive/drug effects , Binding, Competitive/physiology , CHO Cells , Clozapine/pharmacology , Cricetinae , Dibenzothiazepines/pharmacology , Dopamine/metabolism , Humans , Olanzapine , Piperazines/pharmacology , Quetiapine Fumarate , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Schizophrenia/physiopathology , Serotonin/metabolism , Serotonin 5-HT1 Receptor Agonists , Serotonin 5-HT1 Receptor Antagonists , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Thiazoles/pharmacologyABSTRACT
Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.
Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Dopamine D2 Receptor Antagonists , Piperazines/pharmacology , Quinolones/pharmacology , Receptors, Dopamine D2/agonists , Amphetamine , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/toxicity , Aripiprazole , Binding, Competitive , Biotransformation , CHO Cells , Catalepsy/chemically induced , Cricetinae , Cricetulus , Dyskinesia, Drug-Induced/etiology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , HeLa Cells , Humans , Male , Motor Activity/drug effects , Oxidopamine , Piperazines/metabolism , Piperazines/toxicity , Quinolones/metabolism , Quinolones/toxicity , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Species Specificity , TransfectionABSTRACT
We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
Subject(s)
Receptors, Chemokine/antagonists & inhibitors , Receptors, Chemokine/metabolism , Amino Acid Substitution , Animals , Binding Sites , Binding, Competitive , CHO Cells , Cattle , Cell Line , Chemotaxis/drug effects , Cricetinae , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Kinetics , Models, Molecular , Monocytes/drug effects , Monocytes/physiology , Mutagenesis, Site-Directed , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Radioligand Assay , Receptors, CCR2 , Receptors, Chemokine/chemistry , Receptors, Chemokine/genetics , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Rhodopsin/chemistry , Rhodopsin/genetics , Structural Homology, Protein , TransfectionABSTRACT
1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.
Subject(s)
Phenols/pharmacokinetics , Pyrrolidines/pharmacokinetics , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacokinetics , Serotonin/analogs & derivatives , Sleep, REM/drug effects , Sleep, REM/physiology , Animals , CHO Cells , Cell Line , Cell Membrane/physiology , Cricetinae , Cyclic AMP/metabolism , Drug Administration Routes , Gene Expression Regulation , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Guinea Pigs , Humans , Hypothermia/chemically induced , Phenols/administration & dosage , Pyrrolidines/administration & dosage , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/genetics , Serotonin/administration & dosage , Serotonin/pharmacokinetics , Serotonin/pharmacology , Serotonin/physiology , Serotonin Antagonists/administration & dosage , TritiumABSTRACT
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Indicators and Reagents , Isoenzymes/drug effects , Models, Molecular , Structure-Activity RelationshipABSTRACT
A focused SAR study around the previously reported selective 5-HT(7) receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.
