Targeting the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT 2C R-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2carboxamide scaffold, we optimized the undecyl moiety at the 4position with variations of cyclohexyl-or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT 2C R PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT 2C R agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT 2C R PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.
New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
High novelty seeking increases the risk for drug experimentation and locomotor sensitization. Locomotor sensitization to psychostimulants is thought to reflect neurological adaptations that promote the transition to compulsive drug taking. Rats reared in enrichment (EC) show less locomotor sensitization when compared to rats reared in isolation (IC) or standard conditions (SC). The current research study was designed to test if novelty response contributed locomotor sensitization and more importantly, if the different housing environments could change the novelty response to protect against the development of locomotor sensitization in both adolescence and adulthood.
Experiment 1: rats were tested for their response to novelty using the inescapable novelty test (IEN) and pseudorandomly assigned to enriched (EC), isolated (IC), or standard (SC) housing conditions for 30 days. After housing, they were tested with IEN. Rats were then administered amphetamine (0.5 mg/kg) or saline and locomotor activity was measured followed by a sensitization test 14 days later. Experiment 2: rats were tested in the IEN test early adulthood and given five administrations of amphetamine (0.3 mg/kg) or saline and then either stayed in or switched housing environments for 30 days. Rats were then re-tested in the IEN test in late adulthood and administered five more injections of their respective treatments and tested for locomotor sensitization.
Results indicate that IC and SC increased the response to novelty. EC housing decreased locomotor response to amphetamine and saline, and SC housing increased the locomotor response to amphetamine. Mediation results indicated that the late adult novelty response fully mediates the locomotor response to amphetamine and saline, while the early adulthood novelty response did not.
Conclusions
Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce drug vulnerability.
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