title: Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport.
abstract: 2-Aminoethyl diphenylborinate (2-APB) is a known modulator of the IP3 receptor, the calcium ATPase SERCA, the calcium release-activated calcium channel Orai and TRP channels. More recently, it was shown that 2-APB is an efficient inhibitor of the epithelial calcium channel TRPV6 which is overexpressed in prostate cancer. We have conducted a structure-activity relationship study of 2-APB congeners to understand their inhibitory mode of action on TRPV6. Whereas modifying the aminoethyl moiety did not significantly change TRPV6 inhibition, substitution of the phenyl rings of 2-APB did. Our data show that the diaryl borinate moiety is required for biological activity and that the substitution pattern of the aryl rings can influence TRPV6 versus SOCE inhibition. We have also discovered that 2-APB is hydrolyzed and transesterified within minutes in solution.
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hofer
authors.forename: Gergely
authors.initials: G
authors.lastname: Kovacs
authors.forename: Anna
authors.initials: A
authors.lastname: Zappatini
authors.forename: Michele
authors.initials: M
authors.lastname: Leuenberger
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
authors.forename: Martin
authors.initials: M
authors.lastname: Lochner
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human; D002118:Calcium