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Synthèse et évaluation de dérivés tétrahydroisoquinoléine-hydantoïne comme ligands sélectifs des récepteurs sigma 1

Abstract : The sigma receptors were described for the first time by Martin and co-workers in 1976. There are 2 subtypes: sigma 1 and sigma 2. Sigma 1 proteins are located in numerous peripheral organs and are especially concentrated in the central nervous system. It is well known that they modulate the transmission of neurotransmitters such as norepinephrine, dopamine, serotonin, acetylcholine, and glutamate as well as the activity of opiate receptors. Consequently, they are associated with some functions or disorders, the origin of which is a dysregulation of these neurotransmitters. Therefore, they affect certain functions such as nociception, cocaine addiction, mnesic disorder, epilepsy and are implicated in neuroprotection. They are also involved in a lot of behaviours in connection with the neuropsychiatric and neurological disorders such as schizophrenia, depression, anxiety. Furthermore, sigma 1 proteins are overexpressed in tumoral cells, which makes them a possible target in cancer treatment. A collaboration was initiated with the laboratory of Dr T. Maurice in Montpellier in order to estimate the activity of our compounds on the effects induced by cocaine.
Previous studies in our laboratory evidenced the affinity of compounds containing the tetrahydroisoquinoline-hydantoin structure (Tic-hydantoin) toward sigma 1 receptors. Based on previous pharmacomodulations and the model of Ablordeppey and Glennon, a compound presenting a good affinity for sigma 1 (IC50 = 9nM), a good selectivity and a weak toxicity, had been discovered.
The purpose of the project was to continue the pharmacomodulation studies around this hit, in order to increase the affinity and the selectivity towards sigma 1 but also to study the structure-activity relationships of our hit compound. On the one hand, studies were carried out on the Tic-hydantoin structure while keeping the side chain intact. On the other hand modifications were applied to the side chain while retaining the native Tic-hydantoin structure.
The stereochemistry of the asymmetric carbon and the replacement of the hydantoin by a thiohydantoin were evaluated at first. Other pharmacomodulations were then realized around the Tic-hydantoin core. Notably, by studying the impact on the affinity towards sigma 1, of an opening of the quinoline ring, of the substitution of this core by a pyridine or a tetraline, of the modification of the connection between the hydantoin and the quinoline and of a functionalisation of the quinoline. Regarding the side chain, we estimated the importance of a functionalisation of the aromatic ring, the small group on the nitrogen, necessary according to Ablordeppey's pharmacophore and finally the importance of a stiffening of the side chain.
Finally, we estimated the anti-cocaine effects of two molecules on behavioural tests on mice. We evaluated the two compounds on three characteristic tests in the study of drugs: (1) the cocaine-induced lomocotor stimulation and sensitization, (2) the acquisition and reactivation of cocaine-induced conditioned place preference test (CPP) and (3) the cocaine-induced memory state. The data collected showed that the two compounds present the same effect but it is more pronounced for one compound. This compound displays a typical sigma 1 receptor agonist profile. It facilitated cocaine-induced psychostimulant and appetitive effects, without inducing such effects when injected alone. Finally, at behavioural sub-active doses, the compound failed to constrain memory by itself but amplified the cocaine-induced chemical state. In other words the compound presents, in mice, the ideal pharmacological profile to be tested as a new agonist therapy.
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https://tel.archives-ouvertes.fr/tel-00326915
Contributor : Marion Toussaint <>
Submitted on : Monday, October 6, 2008 - 2:49:33 PM
Last modification on : Thursday, February 21, 2019 - 10:34:03 AM
Long-term archiving on: : Friday, June 4, 2010 - 12:15:22 PM

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  • HAL Id : tel-00326915, version 1

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Marion Toussaint. Synthèse et évaluation de dérivés tétrahydroisoquinoléine-hydantoïne comme ligands sélectifs des récepteurs sigma 1. Médicaments. Université du Droit et de la Santé - Lille II, 2008. Français. ⟨tel-00326915⟩

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