ABSTRACT
A recent neuroimaging study in adults found that the occipital place area (OPA)-a cortical region involved in "visually guided navigation" (i.e. moving about the immediately visible environment, avoiding boundaries, and obstacles)-represents visual information about walking, not crawling, suggesting that OPA is late developing, emerging only when children are walking, not beforehand. But when precisely does this "walking selectivity" in OPA emerge-when children first begin to walk in early childhood, or perhaps counterintuitively, much later in childhood, around 8 years of age, when children are adult-like walking? To directly test these two hypotheses, using functional magnetic resonance imaging (fMRI) in two groups of children, 5- and 8-year-olds, we measured the responses in OPA to first-person perspective videos through scenes from a "walking" perspective, as well as three control perspectives ("crawling," "flying," and "scrambled"). We found that the OPA in 8-year-olds-like adults-exhibited walking selectivity (i.e. responding significantly more to the walking videos than to any of the others, and no significant differences across the crawling, flying, and scrambled videos), while the OPA in 5-year-olds exhibited no walking selectively. These findings reveal that OPA undergoes protracted development, with walking selectivity only emerging around 8 years of age.
Subject(s)
Brain Mapping , Magnetic Resonance Imaging , Child , Child, Preschool , Humans , Brain Mapping/methods , Magnetic Resonance Imaging/methods , Neuroimaging , Photic Stimulation/methods , WalkingABSTRACT
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Subject(s)
Anti-Obesity Agents/chemistry , Cyclohexylamines/chemistry , Pyrimidines/chemistry , Quinazolines/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Administration, Oral , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Eating , Humans , Male , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Weight LossABSTRACT
The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.
Subject(s)
Quinazolines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Quinazolines/chemistry , Quinazolines/pharmacology , Radioligand Assay , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A series of 4-(dimethylamino)quinazoline based antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. This series was derived from a lead compound, AR129330, identified by HTS of a GPCR-directed library using a functional assay with a constitutively activated (CART) form of the receptor. The preliminary optimization resulted in the identification of compounds 20, 21, and 23.