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ABSTRACT:Unbound fractions in mouse brain and plasma were determined for 31 structurally diverse central nervous system (CNS) drugs and two active metabolites. Three comparisons were made between in vitro binding and in vivo exposure data, namely: 1) mouse brainto-plasma exposure versus unbound plasma-to-unbound brain fraction ratio (fu plasma /fu brain ), 2) cerebrospinal fluid-to-brain exposure versus unbound brain fraction (fu brain ), and 3) cerebrospinal fluid-to-plasma exposure versus unbound plasma fraction (fu plasma ). Unbound fraction data were within 3-fold of in vivo exposure ratios for the majority of the drugs examined (i.e., 22 of 33), indicating a predominately free equilibrium across the blood-brain and blood-CSF barriers. Some degree of distributional impairment at either the blood-CSF or the blood-brain barrier was indicated for 8 of the 11 remaining drugs (i.e., carbamazepine, midazolam, phenytoin, sulpiride, thiopental, risperidone, 9-hydroxyrisperidone, and zolpidem). In several cases, the indicated distributional impairment is consistent with other independent literature reports for these drugs. Through the use of this approach, it appears that most CNS-active agents freely equilibrate across the blood-brain and blood-CSF barriers such that unbound drug concentrations in brain approximate those in the plasma. However, these results also support the intuitive concept that distributional impairment does not necessarily preclude CNS activity.

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Significant progress has been made in structurebased drug design by pharmaceutical companies at different stages of drug discovery such as identifying new hits, enhancing molecule binding affinity in hit-to-lead, and reducing toxicities in lead optimization. Drug metabolism is a major consideration for modifying drug clearance and also a primary source for drug metabolite-induced toxicity. With major cytochrome P450 structures identified and characterized recently, structure-based drug metabolism prediction becomes increasingly attractive. In silico methods based on molecular and quantum mechanics such as docking, molecular dynamics and ab initio chemical reactivity calculations bring us closer to understand drug metabolism and predict drug-drug interactions. In this study, we review important progress in drug metabolism and common in silico techniques adopted to predict drug regioselectivity, stereoselectivity, reactive metabolites, induction, inhibition and mechanism-based inactivation, as well as their implementation in hit-to-lead drug discovery.Key words: cytochrome P450, drug design, drug metabolism, structure-based The goal of drug discovery is to find best medicines to prevent, treat and cure diseases quickly and efficiently. To fulfill this goal, computational tools have helped medicinal chemists modify and optimize molecules to potent drug candidates, have led biologists and pharmacologists to explore new disease genes and novel drug targets, and have been also guiding drug metabolism scientists to achieve better pharmacokinetic profiles and avoid drug toxicities. These in silico approaches have been widely applied to predict drug absorption, distribution, metabolism, excretion and toxicity (ADMET). The optimization of chemical space in early discovery stage using these in silico tools will shorten the total drug discovery cycle time and at the same time enhance the late-stage drug survival rate. Lipinski's 'Rule-of-Five' is a rule of thumb to predict small-molecule oral drug bioavailability, which initiated the era of data mining and computer-aided drug design in pharmaceutical industry (1). Another virtual 'prediction' example is the 'structure alert chart' summarized by medicinal chemists for drug design purpose. To develop comprehensive drug metabolism prediction methods will offer a powerful means to identify and analyze potential pharmacokinetic and toxicological problems.Metabolism is a major consideration for modifying drug clearance and a primary source for drug metabolite-induced drug toxicity. An appropriate pharmacokinetic profile such as a reasonable half-life is mainly controlled by drug metabolism, which should be adapted to the desired purpose and is extremely important for drug development. Drug-metabolizing enzymes catalyze phase I (such as hydrolysis, reduction and oxidation) and phase II (such as glucuronidation, sulfation, acetylation, methylation and glutathione conjugation) reactions (2). The oxidation reactions in phase I often cause toxicities and ⁄ or drug-drug interactions. C...

We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.

CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E 2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia. Introduction:The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E 2 (PGE 2 ) agonist, CP432, could produce bone anabolic effects in aged, ovariectomized (OVX) rats with established osteopenia. Materials and Methods: CP432 at 0.3, 1, or 3 mg/kg/day was given for 6 weeks by subcutaneous injection to 12-month-old rats that had been OVX for 8.5 months. The effects on bone mass, bone formation, bone resorption, and bone strength were determined. Results: Total femoral BMD increased significantly in OVX rats treated with CP432 at all doses. CP432 completely restored trabecular bone volume of the third lumbar vertebral body accompanied with a dosedependent decrease in osteoclast number and osteoclast surface and a dose-dependent increase in mineralizing surface, mineral apposition rate, and bone formation rate-tissue reference in OVX rats. CP432 at 1 and 3 mg/kg/day significantly increased total tissue area, cortical bone area, and periosteal and endocortical bone formation in the tibial shafts compared with both sham and OVX controls. CP432 at all doses significantly and dose-dependently increased ultimate strength in the fifth lumber vertebral body compared with both sham and OVX controls. At 1 and 3 mg/kg/day, CP432 significantly increased maximal load in a three-point bending test of femoral shaft compared with both sham and OVX controls. Conclusions: CP432 completely restored trabecular and cortical bone mass and strength in established osteopenic, aged OVX rats by stimulating bone formation and inhibiting bone resorption on trabecular and cortical surfaces.

A great deal of current research is focused on the behavior of low molecular weight substances in living systems. Pharmacology, molecular toxicology, neuroscience, nutrition, energy metabolism, and fermentation are among the fields in which monitoring chemical changes in the environment of living cells is crucial.The living systems of interest may reasonably be described as islands REPORT full of life in a dead chemical sea, and the transport of substances to and from the islands can tell much about the activities therein. Pipes running through the sea frequently deliver and remove the chemical inventory.Changes take place with time constants that range from less than a millisecond to more than a year. The challenges for analytical chemists in measuring these changes are substantial. Microdialysis sampling is a powerful new technique for the study of in vivo pharmacokinetics and the metabolism of drugs. Interest in this area is burgeoning, as demonstrated by the large attendance at the second International Symposium on Microdialysis Sampling, which was held in Indianapolis, IN, May 15-17, 1991. There were more than 80 presentations describing a variety of