ABSTRACT
A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D(2) ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D(2) partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D(2) affinity, function, and SRI activity.
Subject(s)
Antipsychotic Agents/chemistry , Dopamine Agonists/chemistry , Quinolones/chemistry , Schizophrenia/drug therapy , Selective Serotonin Reuptake Inhibitors/chemistry , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/therapeutic use , Disease Models, Animal , Dopamine Agonists/chemical synthesis , Dopamine Agonists/therapeutic use , Quinolones/chemical synthesis , Quinolones/therapeutic use , Receptor, Serotonin, 5-HT1A/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/therapeutic use , Structure-Activity RelationshipABSTRACT
A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.
Subject(s)
Carbazoles/chemistry , Dopamine Agonists/chemistry , Receptors, Dopamine D2/agonists , Schizophrenia/drug therapy , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin 5-HT1 Receptor Antagonists , Animals , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Disease Models, Animal , Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D2/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
We have investigated a series of 7-azaindoles as potential partial agonists of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM). Compound 30A demonstrated both moderate binding affinity and partial agonist potency, thus representing a promising lead for the indications of cognition and smoking cessation.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Alkaloids/chemistry , Alkaloids/metabolism , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Azocines/chemistry , Azocines/metabolism , Brain/metabolism , Indoles/chemical synthesis , Indoles/pharmacokinetics , Kinetics , Neurons/metabolism , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacokinetics , Quinolizines/chemistry , Quinolizines/metabolism , Radioligand Assay , Rats , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/metabolismABSTRACT
The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
Subject(s)
Antipsychotic Agents/chemistry , Benzoxazines/chemistry , Indoles/chemistry , Phthalimides/chemistry , Piperazines/chemistry , Pyridines/chemistry , Receptors, Biogenic Amine/chemistry , Antipsychotic Agents/adverse effects , Antipsychotic Agents/metabolism , Basal Ganglia Diseases/chemically induced , Benzoxazines/adverse effects , Benzoxazines/metabolism , Biogenic Monoamines/metabolism , Humans , Hyperprolactinemia/chemically induced , Indoles/adverse effects , Indoles/metabolism , Metabolic Diseases/chemically induced , Phthalimides/adverse effects , Phthalimides/metabolism , Piperazines/adverse effects , Piperazines/metabolism , Principal Component Analysis , Pyridines/adverse effects , Pyridines/metabolism , Radioligand Assay , Receptors, Biogenic Amine/metabolism , Weight GainABSTRACT
Combined dopamine D(2) receptor antagonism and serotonin (5-HT)(1A) receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D(2/3) antagonist and 5-HT(1A) agonist. SLV313 possessed high affinity at human recombinant D(2), D(3), D(4), 5-HT(2B), and 5-HT(1A) receptors, moderate affinity at 5-HT(7) and weak affinity at 5-HT(2A) receptors, with little-no affinity at 5-HT(4), 5-HT(6), alpha(1), and alpha(2) (rat), H(1) (guinea pig), M(1), M(4), 5-HT(3) receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT(1A) receptors (pEC(50)=9.0) and full antagonist activity at hD(2) (pA(2)=9.3) and hD(3) (pA(2)=8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT(1A) syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT(1A) antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT(1A)-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT(1A) receptor agonist and full D(2/3) receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.
Subject(s)
Antipsychotic Agents/pharmacology , Dopamine D2 Receptor Antagonists , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Agonists , Analysis of Variance , Animals , Behavior, Animal/drug effects , Binding, Competitive/drug effects , Brain Chemistry/drug effects , CHO Cells , Catalepsy/drug therapy , Columbidae , Cricetinae , Cricetulus , Discrimination, Psychological/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Humans , Male , Piperazines/chemistry , Rats , Rats, Wistar , Serotonin Receptor Agonists/pharmacology , TransfectionABSTRACT
Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.
