title: Synthesis and Biological Evaluation of Pentacycloundecylamines and Triquinylamines as Voltage-Gated Calcium Channel Blockers.
abstract: Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca(2+) overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca(2+) overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall, 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6) .0(3,10) .0(5,9) ]undecane (NGP1-01, 7a) had the most favorable pharmacological profile with an IC50 value of 86 µM for LTCC inhibition and significant reduction of hydrogen peroxide-induced cell death. In general, the triquinylamines were more active as LTCC blockers than the oxa-pentacycloundecylamines. The aza-pentacycloundecylamines were potent LTCC inhibitors, with 8-hydroxy-N-phenylethyl-8,11-azapentacyclo[5.4.0.0(2,6) .0(3,10) .0(5,9) ]undecane (8b) also able to offer significant protection in the cell viability assays.
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
authors.forename: Lois-May
authors.initials: LM
authors.lastname: Young
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
authors.forename: Olwen C
authors.initials: OC
authors.lastname: Domingo
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.|School of Pharmacy, University of the Western Cape, Bellville, South Africa.
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, ID, USA.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006840:Hydrocarbons, Alicyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016716:PC12 Cells; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D006840:Hydrocarbons, Alicyclic; D011809:Quinones; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002118:Calcium
keywords: L-type calcium channel (LTCC) blockers; Multifunctional drugs; Neurodegeneration; Pentacycloundecylamine; Triquinylamine