title: Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats.
abstract: Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D(4) receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D(4) receptor agonist that activates human dopamine D(4) receptors with an EC(50) of 12.4 nM and 61% efficacy, with no effect on dopamine D(1), D(2), D(3), or D(5) receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. jorge.brioni@abbott.com
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Marlon
authors.initials: M
authors.lastname: Cowart
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
authors.forename: Diana L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: James J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Teodozyi
authors.initials: T
authors.lastname: Kolasa
authors.forename: James S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Osinski
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Andersson
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004294:Domperidone / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010410:Penile Erection / Q000187:drug effects*; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050638:Receptors, Dopamine D4; D011994:Recombinant Proteins / Q000819:agonists
chemical_list: C487766:ABT724; D001562:Benzimidazoles; C493599:DRD4 protein, human; D018491:Dopamine Agonists; C493601:Drd4 protein, rat; D010879:Piperazines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D050638:Receptors, Dopamine D4; D004294:Domperidone; D006220:Haloperidol