ABSTRACT
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Drug Design , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Adrenergic Uptake Inhibitors/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Cell Line , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Phenols/chemical synthesis , Phenols/metabolism , Phenols/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacologyABSTRACT
Irradiation of 9,9'-bifluorene-9,9'-diol (1) gave 9-fluorenone and spiro[9H-fluorene-9,9'(10'-H)-phenanthren]-10'-one (4), the latter arising from a pinacol rearrangement. The distribution of fluorenone and ketone 4 was solvent dependent with the latter being the major product in trifluoroethanol, a solvent known to stabilize carbocation intermediates. Laser flash photolysis of diol 1 in 2,2,2-trifluoroethanol or hexafluoro-2-propanol showed two transients absorbing at 350 and 505 nm with a weak band at 700 nm. The latter two peaks are assigned to the corresponding substituted 9-fluorenyl cation (5) formed from photoheterolysis of diol 1. Comparison of the decay kinetics between cation 5 and other 9-fluorenyl cations, the parent 9-fluorenyl and 9-phenyl-9-fluorenyl cations, showed that the decay of 5 was relatively insensitive to the nature of the solvent as compared to the latter two carbocations suggesting that unimolecular rearrangement in 5 competes with nucleophilic quenching.
