Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

Use of short high-performance liquid chromatography columns and tandem-mass spectrometry for the rapid analysis of a prostaglandin analog, fluprostenol, in rat plasma.

A short reversed-phase HPLC column and a tandem mass spectrometer were used to develop a stable-isotope-dilution assay for the rapid and sensitive analysis of fluprostenol, a prostaglandin analog, in rat plasma. A Waters Symmetry ODS column (2.1x10 mm) afforded rapid isocratic elution of fluprostenol (t(R)=40 s) but still provided a relatively large k' value of 4. The use of tandem mass spectrometry allowed the interference-free detection of fluprostenol under the rapid elution conditions, with a limit of quantitation of 25 pg ml(-1) fluprostenol, using 0.2 ml plasma sample volumes. The method was linear over three orders of magnitude, yielded accurate and precise results and allowed the pharmacokinetic profile of fluprostenol to be defined following intravenous administration in rats.

A reevaluation of stimulus overselectivity: restricted stimulus control or stimulus control hierarchies.

Stimulus overselectivity, previously described as restricted stimulus control, was examined in preschool children. Twenty-seven subjects, after being trained to respond to a two-component auditory stimulus (S+) and not to respond to a different two-component auditory stimulus (S-), were tested to determine which stimulus elements of the complexes exerted control. Subjects that met the operational definition of overselectivity were found to have exhibited a hierarchy of stimulus control. What differentiated the subjects who would not be labeled "overselective" from those who would be was the placement of S+ and S- elements within the hierarchy, not that one type of subject had restricted stimulus control and another did not. The results indicate that the current conception of stimulus overselectivity may require revision. Treatment and research implications are discussed.

Effects of criterion-level probing on demonstrating newly acquired discriminative behavior.

The purpose of the study was to determine whether probes of the final criterion-level discrimination administered during and after training provided an accurate measure of acquisition. Training and probe stimuli were designed to make training and probe trials initially very discriminable and then progressively less discriminable as training progressed. Initially, the discrimination required on probe trials was more difficult than the discrimination required on training trials. However, this difference in difficulty was gradually eliminated as training stimuli were topographically altered and made identical to probe stimuli by the end of training. Results showed that while correct responding was maintained throughout training, error patterns occurred on all probe trials administered during training. Error patterns developed regardless of whether probe trials occurred only at the beginning of training sessions (temporally discriminable probes) or were randomly interspersed in the training sessions (temporally indiscriminable probes). Probe error patterns seemed to be controlled by the stimulus properties of training and probe trials. Thus, probes did not measure acquisition as it occurred during training. Probe error patterns were maintained when probes were administered after completion of training. This final measure of acquisition did not agree with the demonstration of acquisition provided by the final training trial. The results suggest that probe trials can measure a different stimulus-response relationship from that trained when training starts with an easier or known discrimination and probes involve a final or criterion test of a more difficult or unknown discrimination. Stimulus control of correct responses versus error patterns is discussed.