ABSTRACT
There is an extensive literature on the usage of Blissymbolics in augmentative and alternative communication that contradicts Morin's contention that it fails as an ideography. Morin's notion of "standardization" (target article, sect. X, para. X) is at odds with the highly developed understanding of this notion in linguistics. What Morin seems to have in mind corresponds to the notion of emergence in iterative and multiagent models of language learning.
Subject(s)
Language Development , Linguistics , Humans , Reference StandardsABSTRACT
The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.
Subject(s)
Cyclobutanes/chemical synthesis , Drug Design , Histamine Antagonists/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Histamine H3/metabolism , Animals , Blood Proteins/metabolism , Blood-Brain Barrier/metabolism , Cell Line , Cyclobutanes/pharmacology , Cyclobutanes/toxicity , Dogs , Drinking Behavior/drug effects , High-Throughput Screening Assays , Histamine Antagonists/pharmacology , Histamine Antagonists/toxicity , Humans , In Vitro Techniques , Kidney/metabolism , Lipidoses/chemically induced , Lipidoses/metabolism , Lung/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Phospholipids/metabolism , Protein Binding , Pyrrolidines/pharmacology , Pyrrolidines/toxicity , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Piracetam, a derivative of γ-aminobutyric acid, exerts memory-enhancing and mild anxiolytic effects in human and rodent studies. To examine the drug's behavioral profile further, we assessed its effects on behavioral and endocrine (cortisol) responses of adult zebrafish (Danio rerio)--a novel model species rapidly gaining popularity in neurobehavioral research. Overall, acute piracetam did not affect zebrafish novel tank and light-dark box behavior at mild doses (25-400mg/L), but produced nonspecific behavioral inhibition at 700mg/L. No effects on cortisol levels or inter-/intra-session habituation in the novel tank test were observed for acute or chronic mild non-sedative dose of 200mg/L. In contrast, fish exposed to chronic piracetam at this dose performed significantly better in the cued learning plus-maze test. This observation parallels clinical and rodent literature on the behavioral profile of piracetam, supporting the utility of zebrafish paradigms for testing nootropic agents.
