A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

Although it has often been suggested that chronic pain patients who are receiving workmen's compensation or who have litigation pending are less likely to benefit from treatment, the results of outcome studies of this question conducted by various pain clinics have been inconsistent. We hypothesized that poorer outcome in such patients may be related to the fact that they are less likely to be working and that the inconsistent results in the literature may therefore be explained by variability among studies in the percentages of patients who are receiving compensation (or who have litigation pending) who are also working. We examined the relationships among compensation, litigation, employment, and short- and long-term treatment response in a series of 454 chronic pain patients. Compensation benefits and employment status both predicted poorer short-term outcome in univariate analyses; however, when employment and compensation were jointly used to predict outcome in multiple regression analyses, only employment was significant. In additional analyses, only employment significantly predicted long-term outcome, whereas compensation and litigation did not. Our results suggest that it would be valuable to redirect attention away from the deleterious effects of the 'compensation neurosis' and toward the roles of activity and employment in the treatment and rehabilitation of chronic pain patients.

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A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [125I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H → 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells. The 4‘,7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT K i = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers.