Development of a Highly Potent D₂/D₃ Agonist and a Partial Agonist from Structure–Activity Relationship Study of <i>N</i>⁶‑(2-(4-(1<i>H</i>‑Indol-5-yl)piperazin-1-yl)ethyl)‑<i>N</i>⁶‑propyl-4,5,6,7-tetrahydrobenzo[<i>d</i>]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson’s Disease

Our structure–activity relationship studies with <i>N</i>⁶-(2-(4-(1<i>H</i>-indol-5-yl)­piperazin-1-yl)­ethyl)-<i>N</i>⁶-propyl-4,5,6,7-tetrahydrobenzo­[<i>d</i>]­thiazole-2,6-diamine derivatives led to development of a lead compound (−)-<b>21a</b> which exhibited very high affinity (<i>K</i>_i, D₂ = 16.4 nM, D₃ = 1.15 nM) and full agonist activity (EC₅₀ (GTPγS); D₂ = 3.23 and D₃ = 1.41 nM) at both D₂ and D₃ receptors. A partial agonist molecule (−)-<b>34</b> (EC₅₀ (GTPγS); D₂ = 21.6 (<i>E</i>_max = 27%) and D₃ = 10.9 nM) was also identified. In a Parkinson’s disease (PD) animal model, (−)-<b>21a</b> was highly efficacious in reversing hypolocomotion in reserpinized rats with a long duration of action, indicating its potential as an anti-PD drug. Compound (−)-<b>34</b> was also able to elevate locomotor activity in the above PD animal model significantly, implying its potential application in PD therapy. Furthermore, (−)-<b>21a</b> was shown to be neuroprotective in protecting neuronal PC12 from toxicity of 6-OHDA. This report, therefore, underpins the notion that a multifunctional drug like (−)-<b>21a</b> might have the potential not only to ameliorate motor dysfunction in PD patients but also to modify disease progression by protecting DA neurons from progressive degeneration

Development of a Highly Potent D₂/D₃ Agonist and a Partial Agonist from Structure–Activity Relationship Study of <i>N</i>⁶‑(2-(4-(1<i>H</i>‑Indol-5-yl)piperazin-1-yl)ethyl)‑<i>N</i>⁶‑propyl-4,5,6,7-tetrahydrobenzo[<i>d</i>]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson’s Disease

Our structure–activity relationship studies with <i>N</i>⁶-(2-(4-(1<i>H</i>-indol-5-yl)­piperazin-1-yl)­ethyl)-<i>N</i>⁶-propyl-4,5,6,7-tetrahydrobenzo­[<i>d</i>]­thiazole-2,6-diamine derivatives led to development of a lead compound (−)-<b>21a</b> which exhibited very high affinity (<i>K</i>_i, D₂ = 16.4 nM, D₃ = 1.15 nM) and full agonist activity (EC₅₀ (GTPγS); D₂ = 3.23 and D₃ = 1.41 nM) at both D₂ and D₃ receptors. A partial agonist molecule (−)-<b>34</b> (EC₅₀ (GTPγS); D₂ = 21.6 (<i>E</i>_max = 27%) and D₃ = 10.9 nM) was also identified. In a Parkinson’s disease (PD) animal model, (−)-<b>21a</b> was highly efficacious in reversing hypolocomotion in reserpinized rats with a long duration of action, indicating its potential as an anti-PD drug. Compound (−)-<b>34</b> was also able to elevate locomotor activity in the above PD animal model significantly, implying its potential application in PD therapy. Furthermore, (−)-<b>21a</b> was shown to be neuroprotective in protecting neuronal PC12 from toxicity of 6-OHDA. This report, therefore, underpins the notion that a multifunctional drug like (−)-<b>21a</b> might have the potential not only to ameliorate motor dysfunction in PD patients but also to modify disease progression by protecting DA neurons from progressive degeneration

A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and development of disease-modifying treatment is still an unmet medical need. Considering the implication of free iron­(II) in PD, we report here the design and characterization of a novel hybrid iron chelator, (−)-<b>12</b> (D-607) as a multitarget-directed ligand against PD. Binding and functional assays at dopamine D₂/D₃ receptors indicate potent agonist activity of (−)-<b>12</b>. The molecule displayed an efficient preferential iron­(II) chelation properties along with potent in vivo activity in a reserpinized PD animal model. The compound also rescued PC12 cells from toxicity induced by iron delivered intracellularly in a dose-dependent manner. However, Fe³⁺ selective dopamine agonist 1 and a well-known antiparkinsonian drug pramipexole produced little to no neuroprotection effect under the same experimental condition. These observations strongly suggest that (−)-<b>12</b> should be a promising multifunctional lead molecule for a viable symptomatic and disease modifying therapy of PD

A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and development of disease-modifying treatment is still an unmet medical need. Considering the implication of free iron­(II) in PD, we report here the design and characterization of a novel hybrid iron chelator, (−)-<b>12</b> (D-607) as a multitarget-directed ligand against PD. Binding and functional assays at dopamine D₂/D₃ receptors indicate potent agonist activity of (−)-<b>12</b>. The molecule displayed an efficient preferential iron­(II) chelation properties along with potent in vivo activity in a reserpinized PD animal model. The compound also rescued PC12 cells from toxicity induced by iron delivered intracellularly in a dose-dependent manner. However, Fe³⁺ selective dopamine agonist 1 and a well-known antiparkinsonian drug pramipexole produced little to no neuroprotection effect under the same experimental condition. These observations strongly suggest that (−)-<b>12</b> should be a promising multifunctional lead molecule for a viable symptomatic and disease modifying therapy of PD