Dopamine D3 receptor: A neuroprotective treatment target in Parkinson's disease.

摘要

Dopamine D3 receptor represents a potential novel target for development of drugs to alleviate symptoms in various neuropsychiatric and neurological disorders such as schizophrenia, Parkinson's disease, drugs of abuse, etc. Several experimental data suggest that D3 receptor agonists can provide neuroprotective effects in Parkinson's disease in addition to alleviating motor dysfunctions. Thus, a D3 selective agonist can provide an advantage over D2 selective agonist in terms of slowing the neurodegeneration process. In our attempt to design and develop novel and selective ligand for D3 receptor, we adopted a hybrid structure strategy by combining pharmacophoric elements of 2-aminotetralin and piperazine molecular fragments derived from known dopamine receptor agonist and antagonist molecules. These hybrids exhibited preferential affinity towards D3 receptor. The hydroxyl group in 2-aminotetralin structure was placed in 5, 6, and 7 positions to optimize the positional requirement of this group in our hybrid structure. In vitro binding, functional assay and in vivo pharmacological assay revealed hydroxyl group at 5 position is optimum. One of our 5-Hydroxy lead compounds, D-237 demonstrated high sub nanomolar affinity for D3 receptor in binding and functional assay. Affinity for D3 receptor was greater than its 7-Hydroxy counterpart molecule D-74. D-237 also demonstrated potent in vivo response as well as long duration of action in rat model of PD. Compound D-237, at 5 muM/kg dose, exhibited long duration of action which lasted beyond 12 hours. D-237 was able to induce high number of contra lateral rotations that indicated potent in vivo agonist efficacy of this compound. Various heterocycles as bioisosteric replacement were introduced in the hybrid structure replacing phenolic moiety of the aminotetralin in order to provide metabolic stability to the compounds. In this regard, 2-aminothiazole heterocycle demonstrated high affinity and selectivity for D3 receptor. One of our lead molecules in this series of heterocyclic compounds, D-264 exhibited sub nanomolar affinity as well as more than 250 fold selectivity for D3 receptor in both in vitro binding and GTPgammaS functional assay. D-264 is one of the very few highly potent D3 selective agonist compounds known to date. D-264 was able to produce high degree of contra lateral rotations in 6-OHDA induced unilaterally lesioned rats in rat model of PD which lasted for more than 10 hours with 5 muM/kg dose which indicated its good in vivo agonist efficacy. D-264 was turned out to be full agonist in GTPgammaS binding functional assay whereas D-237 turned out to be potent partial agonist compared to the maximum stimulation of dopamine which is considered to be 100%. Another functional assay, cAMP enzyme immunoassay, was also performed on the lead molecules to prove the functional potency of our compounds. Considering the fact that D3 preferring agonist, apart from providing symptomatic relief, exhibit neuroprotection to the dying neurons of substantia nigra by various ways, we assume D-237 and D-264 will also be able to provide neuroprotection. In depth neuroprotection assay has to be carried out to find out the neuroprotective efficacy of our D3 selective compounds. This work is supported by grants from NINDS (NS 047198).