title: Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity.
abstract: Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.
authors.affiliation: Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA.
authors.forename: Satishkumar
authors.initials: S
authors.lastname: Gadhiya
authors.affiliation: Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA.
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Madapa
authors.affiliation: Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA; Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA; Department of Chemistry, Lehman College, The City University of New York, Bronx, NY 10468, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurtzman
authors.affiliation: Department of Natural Sciences, LaGuardia Community College, City University of New York, New York, NY 11101, USA.
authors.forename: Ian L
authors.initials: IL
authors.lastname: Alberts
authors.affiliation: Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA; Department of Chemistry, Lehman College, The City University of New York, Bronx, NY 10468, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Ramsey
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Nagavara-Kishore
authors.initials: NK
authors.lastname: Pillarsetty
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Teja
authors.initials: T
authors.lastname: Kalidindi
authors.affiliation: Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA; Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA. Electronic address: whardi@hunter.cuny.edu.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Harding
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects*; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D011954:Receptors, Dopamine; D017480:Receptors, sigma; D001599:Berberine
keywords: D3; Dopamine; Sigma; Stepholidine; THPB; Tetrahydroprotoberberine