Drug abuse, addiction, and dependence represent a major and increasing threat to public health. Abuse of amphetamines is wide spread;reaching epidemic proportions both nationally and globally, and is associated with significant health risk. Fortunately, there is an increasing understanding that drug abuse is a physiologic disorder and that the need for medications for the treatment of drug abuse is tremendous. At present however, no pharmacological approaches exist for the treatment of amphetamine abuse. There is however an avenue to explore that may one day provide a means of treating this problem. It has been suggested that drug craving and drug seeking are actually """"""""unwanted"""""""" forms of learning that are acquired when the brain responds to its reward circuitry being hijacked by drugs. This maladaptive behavior is manifested by physical changes to key brain areas mediating reward and learning (neuronal plasticity). The enhancement of locomotor activity observed in rodents following repeated dosing of psychostimulants, known as behavioral sensitization, is thought to represent one form of these maladaptive changes. This has provided researchers with a convenient endpoint for screening compounds for their ability to effect this sensitization reasoning that efficacy here may translate into efficacy against drug seeking and drug craving. Using peptide agonists for the neurotensin receptors (NTR1 and NTR2) it has been possible to suppress psychostimulant sensitization. However, these compounds do not possess receptor selectivity and as a consequence of their action at NTR1, show an unwanted side-effect profile. Interestingly, the nucleus accumbens, the region believed to mediate the expression of sensitization, has only NTR2 receptors suggesting that agonists selective for this receptor subtype may represent a platform for the development of a pharmacotherapy to treat psychostimulant abuse. Our goal is to develop potent and selective small organic molecule neurotensin receptor 2 agonists based on the only known ligand of this type Levocabastine.
| Thomas, James B; Navarro, Hernán; Warner, Keith R et al. (2009) The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay. Bioorg Med Chem Lett 19:1438-41 |
