title: Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: impact on functional activity and selectivity for dopamine D2/D3 receptors.
abstract: The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (K(i)) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, 259 Mack Ave, Detroit, MI 48202, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Gopishetty
authors.forename: Suhong
authors.initials: S
authors.lastname: Zhang
authors.forename: Prashant S
authors.initials: PS
authors.lastname: Kharkar
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.forename: Maarten
authors.initials: M
authors.lastname: Reith
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000737:chemistry; D013134:Spiperone / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D018491:Dopamine Agonists; D009281:Naphthalenes; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013134:Spiperone