ABSTRACT
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
A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.
Subject(s)
Antipsychotic Agents/chemical synthesis , Benzoxazines/chemical synthesis , Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Piperazines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Biological Transport , CHO Cells , Cell Line , Cricetinae , Cricetulus , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Models, Molecular , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
In this paper, SLV310 is presented as a novel, potential antipsychotic displaying the interesting combination of potent dopamine D(2) receptor antagonism and serotonin reuptake receptor inhibition in one molecule. As such, SLV310 could be useful in treating a broad range of symptoms in schizophrenia. This paper describes the structure-activity relationship in a series of compounds leading to SLV310 (6b, 2-[4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl]-phthalimide) together with pharmacological data showing the unique profile of this compound.
