Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats.
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.
Brioni
Jorge D
JD
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. jorge.brioni@abbott.com
Moreland
Robert B
RB
Cowart
Marlon
M
Hsieh
Gin C
GC
Stewart
Andrew O
AO
Hedlund
Petter
P
Donnelly-Roberts
Diana L
DL
Nakane
Masaki
M
Lynch
James J
JJ
Kolasa
Teodozyi
T
Polakowski
James S
JS
Osinski
Mark A
MA
Marsh
Kennan
K
Andersson
Karl-Erik
KE
Sullivan
James P
JP
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
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