ABSTRACT
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Subject(s)
Benzoxazoles/pharmacokinetics , Indoles/pharmacokinetics , Memory Disorders/drug therapy , Muscarinic Agonists/pharmacokinetics , Nootropic Agents/pharmacokinetics , Receptor, Muscarinic M1/metabolism , Animals , Benzoxazoles/chemistry , Benzoxazoles/therapeutic use , Brain/metabolism , Indoles/chemistry , Indoles/therapeutic use , Muscarinic Agonists/chemistry , Muscarinic Agonists/therapeutic use , Nootropic Agents/chemistry , Nootropic Agents/therapeutic use , Oxindoles , RatsABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Subject(s)
Quinolines/pharmacology , Receptors, Serotonin, 5-HT1/drug effects , Administration, Oral , Animals , Biological Availability , Ligands , Quinolines/administration & dosage , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.
