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Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase.

ABSTRACT: Combining computer-assisted drug design and synthetic efforts, we generated compounds with potent and balanced activities toward both D3 dopamine receptor and fatty acid amide hydrolase (FAAH) enzyme. By concurrently modulating these targets, our compounds hold great potential toward exerting a disease-modifying effect on nicotine addiction and other forms of compulsive behavior.

SUBMITTER: De Simone A

PROVIDER: S-EPMC4038168 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase.

De Simone Alessio A Ruda Gian Filippo GF Albani Clara C Tarozzo Glauco G Bandiera Tiziano T Piomelli Daniele D Cavalli Andrea A Bottegoni Giovanni G

Chemical communications (Cambridge, England) 20140501 38

Combining computer-assisted drug design and synthetic efforts, we generated compounds with potent and balanced activities toward both D3 dopamine receptor and fatty acid amide hydrolase (FAAH) enzyme. By concurrently modulating these targets, our compounds hold great potential toward exerting a disease-modifying effect on nicotine addiction and other forms of compulsive behavior. ...[more]

PMID: 24691497

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Project description:Slow-timescale (tonic) changes in dopamine (DA) contribute to a wide variety of processes in reinforcement learning, interval timing, and other domains. Furthermore, changes in tonic DA exert distinct effects depending on when they occur (e.g., during learning vs. performance) and what task the subject is performing (e.g., operant vs. classical conditioning). Two influential theories of tonic DA-the average reward theory and the Bayesian theory in which DA controls precision-have each been successful at explaining a subset of empirical findings. But how the same DA signal performs two seemingly distinct functions without creating crosstalk is not well understood. Here we reconcile the two theories under the unifying framework of 'rational inattention,' which (1) conceptually links average reward and precision, (2) outlines how DA manipulations affect this relationship, and in so doing, (3) captures new empirical phenomena. In brief, rational inattention asserts that agents can increase their precision in a task (and thus improve their performance) by paying a cognitive cost. Crucially, whether this cost is worth paying depends on average reward availability, reported by DA. The monotonic relationship between average reward and precision means that the DA signal contains the information necessary to retrieve the precision. When this information is needed after the task is performed, as presumed by Bayesian inference, acute manipulations of DA will bias behavior in predictable ways. We show how this framework reconciles a remarkably large collection of experimental findings. In reinforcement learning, the rational inattention framework predicts that learning from positive and negative feedback should be enhanced in high and low DA states, respectively, and that DA should tip the exploration-exploitation balance toward exploitation. In interval timing, this framework predicts that DA should increase the speed of the internal clock and decrease the extent of interference by other temporal stimuli during temporal reproduction (the central tendency effect). Finally, rational inattention makes the new predictions that these effects should be critically dependent on the controllability of rewards, that post-reward delays in intertemporal choice tasks should be underestimated, and that average reward manipulations should affect the speed of the clock-thus capturing empirical findings that are unexplained by either theory alone. Our results suggest that a common computational repertoire may underlie the seemingly heterogeneous roles of DA.

Dataset Information

Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase.

Publications

Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase.

Similar Datasets

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