title: Sigma1 recognition sites in rabbit iris-ciliary body: topical sigma1-site agonists lower intraocular pressure.
abstract: In this study, we examined the presence of sigma1 and sigma2 sites in the rabbit iris-ciliary body by receptor binding and investigated their effects on intraocular pressure (IOP) in albino rabbits. The iris-ciliary body has binding sites for the sigma1-site agonist [3H](+)-pentazocine (Kd = 4.6 nM; Bmax = 212 fmol/mg protein) and sigma2 sites labeled with [3H]1,3-di-o-tolylguanidine (DTG) (Kd = 8. 2 nM; Bmax = 1120 fmol/mg protein). In competition binding studies, (+)-pentazocine and the sigma antagonist NE-100 displayed high affinity for sigma1 sites (Ki = 2.1 and 2.4 nM, respectively), whereas (+)-N-allylnormetazocine (NANM) was less potent (Ki = 178 nM). Unilateral topical (+)-pentazocine (0.01-0.1%) caused a significant dose-related reduction of IOP in ocular normotensive rabbits and in the alpha-chymotrypsin model of ocular hypertension. (+)-NANM was less potent than (+)-pentazocine. Neither compound altered the IOP of the contralateral eye, and their hypotensive activity was blocked by NE-100 that, by itself, had no effect on IOP. (-)-Pentazocine, (-)-NANM, and DTG had no effect on IOP. DTG prevented the hypotensive effect of (+)-pentazocine, suggesting that it acts as a sigma1-site antagonist. sigma-Site ligands did not affect pupil diameter or cause ocular inflammation. Topical [3H](+)-pentazocine reaches the intraocular tissues within 30 min, and its uptake in the iris-ciliary body and retina was significantly reduced by topical pretreatment with NE-100, as expected for a receptor-specific agent. Reverse-phase HPLC confirmed the presence of intact (+)-pentazocine in iris-ciliary body homogenates. sigma1-Site agonists may offer a novel class of agents potentially effective in the control of ocular hypertension.
authors.affiliation: Department of Pharmacology, University of Bologna, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bucolo
authors.forename: G
authors.initials: G
authors.lastname: Campana
authors.forename: R
authors.initials: R
authors.lastname: Di Toro
authors.forename: S
authors.initials: S
authors.lastname: Cacciaguerra
authors.forename: S
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002924:Ciliary Body / Q000187:drug effects / Q000502:physiology*; D007839:Functional Laterality; D006146:Guanidines / Q000493:pharmacokinetics; D007429:Intraocular Pressure / Q000187:drug effects*; D007498:Iris / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D007908:Lens, Crystalline / Q000187:drug effects / Q000502:physiology; D008297:Male; D010423:Pentazocine / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D011817:Rabbits; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000502:physiology; D014316:Tritium
chemical_list: D000840:Anisoles; D014150:Antipsychotic Agents; D006146:Guanidines; D011437:Propylamines; D017480:Receptors, sigma; D014316:Tritium; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C012134:SK&F 10047; D010620:Phenazocine; C050232:1,3-ditolylguanidine; D010423:Pentazocine