ABSTRACT
The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonist with enhanced CNS exposure.
Subject(s)
Pyrimidines/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Spiro Compounds/chemistry , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacokinetics , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Animals , Central Nervous System/drug effects , Humans , Microsomes, Liver/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Receptors, Neuropeptide Y/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
BACKGROUND: The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. RESULTS: We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. CONCLUSION: Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control.
