title: A class of sulfonamide carbonic anhydrase inhibitors with neuropathic pain modulating effects.
abstract: A series of benzene sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors which incorporate lipophilic 4-alkoxy- and 4-aryloxy moieties, together with several derivatives of ethoxzolamide and sulfanilamide are reported. These derivatives were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) of which multiple isoforms are known, and some appear to be involved in pain. These sulfonamides showed modest inhibition against the cytosolic isoform CA I, but were generally effective, low nanomolar CA II, VII, IX and XII inhibitors. X-ray crystallographic data for the adduct of several such sulfonamides with CA II allowed us to rationalize the good inhibition data. In a mice model of neuropathic pain induced by oxaliplatin, one of the strong CA II/VII inhibitors reported here induced a long lasting pain relieving effect, a fact never observed earlier. This is the first report of rationally designed sulfonamide CA inhibitors with pain effective modulating effects.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.affiliation: Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Farmacologia, Viale G. Pieraccini 6, 50139 Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Pinard
authors.affiliation: Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Farmacologia, Viale G. Pieraccini 6, 50139 Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D002256:Carbonic Anhydrases
keywords: Analgesic; Carbonic anhydrase; Metalloenzyme; Pain; Sulfonamide; X-ray crystallography