title: Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure-Activity Relationship Study of N(6)-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson's Disease.
abstract: Our structure-activity relationship studies with N(6)-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives led to development of a lead compound (-)-21a which exhibited very high affinity (Ki, 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 (-)-34 (EC50 (GTPγS); D2 = 21.6 (Emax = 27%) and D3 = 10.9 nM) was also identified. In a Parkinson's disease (PD) animal model, (-)-21a was highly efficacious in reversing hypolocomotion in reserpinized rats with a long duration of action, indicating its potential as an anti-PD drug. Compound (-)-34 was also able to elevate locomotor activity in the above PD animal model significantly, implying its potential application in PD therapy. Furthermore, (-)-21a 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 (-)-21a 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.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Banibrata
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Seenuvasan
authors.initials: S
authors.lastname: Vedachalam
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Luo
authors.affiliation: Department of Psychiatry, New York University , New York, New York 10016, United States.
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.affiliation: Department of Psychiatry, New York University , New York, New York 10016, United States.|Department of Biochemistry and Molecular Pharmacology, New York University , New York, New York 10016, United States.
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C540567:2-amino-4,5,6,7-tetrahydrobenzothiazole; D000978:Antiparkinson Agents; D052160:Benzothiazoles; D018696:Neuroprotective Agents; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3