![]() In diet-induced obese rats, selective mobilization of fat, maintenance of body protein, and decreased energetic efficiency were also observed. ![]() Dose-related reductions were observed in: 1) glucose-induced insulin secretion 2) basal insulin concentration 3) daily food intake and 4) bodyweight gain. The effects of oral administration of Ro 23-7637 were assessed in Zucker and diet-induced obese rats in doses ranging from 5 to 90 mg/kg/day. When islets from lean rats were exposed to Ro 23-7637, no reduction in insulin secretion was observed. When islets were cultured for 2 days with 10 microM Ro 23-7637, a significant reduction in the exaggerated glucose-induced insulin secretion was observed. To test this hypothesis, the activity of Ro 23-7637, (4-(2,2-diphenylethenyl)-1-piperidine), which partially normalizes plasma insulin by an action on pancreatic islets from obese rats, was assessed. If hyperinsulinemia plays a critical role as proposed, then its reversal may have therapeutic potential. However, the role of hyperinsulinemia in the etiology and maintenance of obesity has been controversial. Hyperinsulinemia and exaggerated insulin response to glucose are among the hallmarks of obesity. The present work thus broadens the scope of structures that may be considered as lead structures in the search for cocaine abuse medications. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments. This smaller spread in binding affinities for the piperidines may reflect the smaller size of these molecules relative to the tropanes, which allows both the cis and the trans isomers to adjust themselves to the binding site on the DAT. This result stands in sharp contrast to the data reported for the tropane series, for the epimerization of the substituent at C-2 from β to α has been reported to result in a lowering of activity by 30−200-fold. As a further point of interest, it was found that the cis-disubstituted piperidine (−)-3 is only about 2-fold more potent than its trans isomer (+)-11. Although no efforts have presently been made to “optimize” binding affinity at the DAT, the substantive activity found for the n-propyl derivative (−)-9 is remarkable the compound is only about 10-fold less active than the best of the high-affinity tropanes of the WIN series. This simple piperidine is thus 33-fold more potent than cocaine in binding affinity and 29-fold more potent in its inhibition of dopamine uptake. Of all of the compounds synthesized, the 3-n-propyl derivative (−)-9 was found to be the most potent with a binding affinity of 3 nM. Interestingly, we have found that these piperidines do, in fact, exhibit substantial affinity in both WIN 35,428 binding at the dopamine transporter and in the inhibition of dopamine uptake. All members of this class were synthesized starting from arecoline hydrobromide and obtained in optically pure form through resolution methods using either (+)- or (−)-dibenzoyltartaric acid. These compounds are piperidine-3-carboxylic acid esters bearing a 4-chlorophenyl group in position 4, and as such, these structures may be viewed as truncated versions of the WIN series compounds, i.e., they lack the two-carbon bridge of the tropanes. in 1973 and that was and shown to lack locomotor stimulatory activity in mice. To discover agents that might be useful in the treatment of cocaine abuse, we have chosen to re-explore a class of molecules that was first reported by Clarke et al.
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