Among the potential therapeutic targets for the development of cognitive enhancers for AD and schizophrenia, the 5-HT 6 receptor is of especial interest based on its localization, pharmacology, and recent behavioral data showing that 5-HT 6 receptor blockade improves cognition in a number of rodent behavioral models. It is localized almost exclusively in the CNS, in areas important for learning and memory, while atypical antipsychotics and tricyclic antidepressants bind with high affinity to this target. 5-HT 6 receptor antagonism enhances neurotransmission at cholinergic and glutamatergic neurons, as well as in other pathways. 5-HT 6 antagonist medicinal chemistry and potential therapeutic applications for treatment of cognitive dysfunction is broadly reviewed. Drug Dev Res 70 : 2009 r 2009 Wiley-Liss, Inc.
Synthesis of 2,3-substituted indoles from phenylhydrazine and alpha-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported. [reaction: see text]
There is an increasing amount of evidence to support that activation of the metabotropic glutamate receptor 4 (mGlu4 receptor), either with an orthosteric agonist or a positive allosteric modulator (PAM), provides impactful interventions in diseases such as Parkinson's disease, anxiety, and pain. mGlu4 PAMs may have several advantages over mGlu4 agonists for a number of reasons. As part of our efforts in identifying therapeutics for central nervous system (CNS) diseases such as Parkinson's disease, we have been focusing on metabotropic glutamate receptors. Herein we report our studies with a series of tricyclic thiazolopyrazoles as mGlu4 PAMs.
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