Development of Neurotensin(8-13) Analogs as Potent NTS1/NTS2 Receptor Ligands with Enhanced Effects on a Mouse Model of Parkinson’s Disease

The tridecapeptide Neurotensin (NT, 1) is widely expressed throughout the central nervous system (CNS) and periphery [1,2].NT exerts its neurophysiological effects mainly by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2) [1].In the brain, NT modulates directly or indirectly dopamine (DA) neurotransmission through different neuronal mechanisms, including antagonistic NT/D2 receptor interaction and second messenger-dependent receptor alteration [3,4].Moreover, both NTS1 and NTS2 receptors are also found in high concentrations on dopaminergic neurons in substantia nigra (SN), suggesting that the activation of both NTS1 and NTS2 receptors in this brain region by NT may stimulate the DA release [3,4].Accordingly, the main effect of NT binding in SN is a D2 autoreceptor inhibition with a subsequent increase of DA signaling [5,6].Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of Parkinson's disease (PD).In the current study we aim at: Developing NT(8-13) peptidomimetics by using virtually guided two-step protein structure homology/molecular modelling approach (Fig. 1 and2, Scheme 1, and Table 1) [2].