The development of combinatorial chemistry and parallel synthesis allow chemists to synthesize small quantities of relatively pure compounds at rates of a few hundred per week per chemist, in contrast to at least a gram of material for a few compounds per month in previous times. With the parallel development of quantitative structure-activity relationship (SAR) techniques, calculated predictions for oral bioavailability and metabolism, and high-throughput screening (HTS) to directly test compounds in 384-well plates, optimal chemical structures for a primary assay can be achieved in a few months with fewer chemists. These techniques have increased efforts to identify second-generation drugs with improved potency, receptor selectivity, safety, and oral bioavailability, and longer duration of the effects. These techniques have yielded new structural and mechanism classes of anti-depressants, antipsychotics, anxiolytics, cognition enhancers, sleep modifiers, and analgesics in the past decade. Additional requirements for CNS-active drugs are moderate lipophilicity, oral bioavailability, and permeability through the blood-brain barrier. Nasal sprays or dermal patches on the neck can deliver drugs to the brain and reduce first-pass metabolism of drug molecules labile to metabolism (N-alkyl groups).
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