title: A new therapeutic approach to erectile dysfunction: urotensin-II receptor high affinity agonist ligands.
abstract: Urotensin-II (U-II) is a cyclic peptide that acts through a G protein-coupled receptor (urotensin-II receptor [UTR]) mainly involved in cardiovascular function in humans. The urotensinergic system is also implicated in the urogenital tract. Indeed, U-II relaxes human corpus cavernosum strips and causes an increase in intracavernous pressure (ICP) in rats. In light of this, the U-II/UTR pathway can be considered a new target for the treatment of erectile dysfunction. On this hypothesis, herein we report on two new UTR high affinity-agonists, P5U (H-Asp-c[Pen-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and UPG84(H-Asp-c[Pen-Phe-DTrp-Orn-(pNH 2 ) Phe-Cys]-Val-OH). The effects of P5U and UPG84 were each compared separately with U-II by monitoring the ICP in anesthetized rats. Intracavernous injection of U-II (0.03-1 nmol), P5U (0.03-1 nmol) or UPG84 (0.03-1 nmol) caused an increase in ICP. P5U, in particular, elicited a significant increase in ICP as compared to U-II. The observed effect by using P5U at a dose of 0.1 nmol per rat was comparable to the effect elicited by U-II at a dose of 0.3 nmol. Moreover, UPG84 at the lowest dose (0.03 nmol) showed an effect similar to the highest dose of U-II (1 nmol). Furthermore, UPG84 was found to be more effective than P5U. Indeed, while the lowest dose of P5U (0.03 nmol) did not affect the ICP, UPG84, at the same dose, induced a prominent penile erection in rat. These compounds did not modify the blood pressure, which indicates a good safety profile. In conclusion, UPG84 and P5U may open new perspectives for the management of erectile dysfunction.
authors: Roberta d'Emmanuele
authors: Rd
authors: di Villa Bianca
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano 49, Naples, Italy.
authors: Emma
authors: E
authors: Mitidieri
authors: Erminia
authors: E
authors: Donnarumma
authors: Ferdinando
authors: F
authors: Fusco
authors: Nicola
authors: N
authors: Longo
authors: Giuseppe De
authors: GD
authors: Rosa
authors: Ettore
authors: E
authors: Novellino
authors: Paolo
authors: P
authors: Grieco
authors: Vincenzo
authors: V
authors: Mirone
authors: Giuseppe
authors: G
authors: Cirino
authors: Raffaella
authors: R
authors: Sorrentino
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007172:Erectile Dysfunction / Q000188:drug therapy*; D008024:Ligands; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: D008024:Ligands; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; C000601246:UPG84 peptide; C473142:Uts2r protein, rat; C466635:aspartyl-cyclo(penicillamyl-phenylalanyl-tryptophyl-lysyl-tyrosyl-cysteinyl)valine