Skip to main content

Advertisement

SpringerLink
Log in

Centrally acting drugs for erectile dysfunction: Do they have a future?

  • Published:
Current Sexual Health Reports Aims and scope Submit manuscript

Abstract

Initial placebo-controlled trials with sublingual apomorphine showed promising results for the drug as an option in the pharmacologic management of erectile dysfunction (ED). More recent studies propose poor erectile effects by apomorphine sublingual in patients with diabetes and fewer benefits than sildenafil in patients with ED. In June this year, the European Medicines Agency declared that due to commercial reasons, the marketing authorization for Uprima (Abbott Laboratories, Abbott Park, IL) was not renewed, and the drug is no longer available in the European Union. This does not mean that receptor functions in the central nervous system are uninteresting pharmacologic targets for ED. Experiences with apomorphine sublingual in humans should be acknowledged for a more careful preclinical and clinical characterization of agents with a central nervous system site of action. This article focuses on information obtained from human trials of central acting drugs for ED.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Dula E, Keating W, Siami PF, et al.: Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction. The Apomorphine Study Group. Urology 200, 56:130–135.

  2. Dula E, Bukofzer S, Perdok R, et al.: Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol 2001, 39:558–563.

    Article  PubMed  CAS  Google Scholar 

  3. Von Keitz AT, Stroberg P, Bukofzer S, et al.: A European multicentre study to evaluate the tolerability of apomorphine sublingual administered in a forced dose-escalation regimen in patients with erectile dysfunction. BJU Int 2002, 89:409–415.

    Article  Google Scholar 

  4. Wessells H, Fuciarelli K, Hansen J, et al.: Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol 1998, 160:389–393.

    Article  PubMed  CAS  Google Scholar 

  5. Wessells H, Gralnek D, Dorr R, et al.: Effect of an alphamelanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology 2000, 56:641–646.

    Article  PubMed  CAS  Google Scholar 

  6. Molinoff PB, Shadiack AM, Earle D, et al.: PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci 2003, 994:96–102.

    PubMed  CAS  Google Scholar 

  7. Diamond LE, Earle DC, Rosen RC, et al.: Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res 2004, 16:51–59.

    Article  PubMed  CAS  Google Scholar 

  8. Rosen RC, Diamond LE, Earle DC, et al.: Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT 141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res 2004, 16:135–142.

    Article  PubMed  CAS  Google Scholar 

  9. Andersson KE: Pharmacology of penile erection. Pharmacol Rev 2001, 53:417–450.

    PubMed  CAS  Google Scholar 

  10. Lewis RW, Fugl-Meyer KS, Bosch R, et al.: Epidemiology/risk factors of sexual dysfunction. J Sex Med 2004, 1:35–39.

    Article  PubMed  Google Scholar 

  11. Brioni JD, Moreland RB, Cowart M, et al.: Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci U S A 2004, 101:6758–6763.

    Article  PubMed  CAS  Google Scholar 

  12. Andersson KE, Gemalmaz H, Waldeck K, et al.: The effect of sildenafil on apomorphine-evoked increases in intracavernous pressure in the awake rat. J Urol 1999, 161:1707–1712.

    Article  PubMed  CAS  Google Scholar 

  13. Paredes RG, Agmo A: Has dopamine a physiological role in the control of sexual behavior? A critical review of the evidence. Prog Neurobiol 2004, 73:179–226.

    Article  PubMed  CAS  Google Scholar 

  14. Giuliano F, Rampin O: Central neural regulation of penile erection. Neurosci Biobehav Rev 2000, 24:517–533.

    Article  PubMed  CAS  Google Scholar 

  15. Melis MR, Succu S, Mascia MS, et al.: Extra-cellular dopamine increases in the paraventricular nucleus of male rats during sexual activity. Eur J Neurosci 2003, 17:1266–1272.

    Article  PubMed  Google Scholar 

  16. Argiolas A, Melis MR, Mauri A, Gessa GL: Paraventricular nucleus lesion prevents yawning and penile erection induced by apomorphine and oxytocin but not by ACTH in rats. Brain Res 1987, 421:349–352.

    Article  PubMed  CAS  Google Scholar 

  17. Chen KK, Chan SH, Chang LS, Chan JY: Participation of paraventricular nucleus of hypothalamus in central regulation of penile erection in the rat. J Urol 1997, 158:238–244.

    Article  PubMed  CAS  Google Scholar 

  18. Andersson KE, Wagner G: Physiology of penile erection. Physiol Rev 1995, 75:191–236.

    PubMed  CAS  Google Scholar 

  19. Chen KK, Chan JY, Chang LS: Dopaminergic neurotransmission at the paraventricular nucleus of hypothalamus in central regulation of penile erection in the rat. J Urol 1999, 162:237–242.

    Article  PubMed  CAS  Google Scholar 

  20. Giuliano F, Allard J: Apomorphine SL (Uprima): preclinical and clinical experiences learned from the first central nervous system-acting ED drug. Int J Impot Res 2002, 14(Suppl 1):S53–S56.

    Article  PubMed  Google Scholar 

  21. Matsumoto K, Yoshida M, Andersson KE, Hedlund P: Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum. Br J Pharmacol 2005, 146:259–267.

    Article  PubMed  CAS  Google Scholar 

  22. Mulhall JP, Bukofzer S, Edmonds AL, et al.: An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction. Clin Ther 2001, 23:1260–1271.

    Article  PubMed  CAS  Google Scholar 

  23. Caruso S, Intelisano G, Farina M, et al.: Efficacy and safety of daily intake of apomorphine SL in men affected by erectile dysfunction and mild hyperprolactinemia: a prospective, open-label, pilot study. Urology 2003, 62:922–927.

    Article  PubMed  Google Scholar 

  24. Kongkanand A, Opanuraks J, Tantiwongse K, et al.: Evaluating dose regimens of apomorphine, an open-label study. Int J Impot Res 2003, 15(Suppl 2):S10–12.

    Article  PubMed  CAS  Google Scholar 

  25. Sibley DR: New insights into dopaminergic receptor function using antisense and genetically altered animals. Annu Rev Pharmacol Toxicol 1999, 39:313–341.

    Article  PubMed  CAS  Google Scholar 

  26. D’Aquila PS, Panin F, Cossu M, et al.: Dopamine D1 receptor agonists induce penile erections in rats. Eur J Pharmacol 2003, 460:71–74.

    Article  PubMed  CAS  Google Scholar 

  27. Moreland RB, Patel M, Hsieh GC, et al.: A-412997 is a selective dopamine D4 receptor agonist in rats. Pharmacol Biochem Behav 2005, 82:140–147.

    Article  PubMed  CAS  Google Scholar 

  28. Melis MR, Succu S, Mascia MS, Argiolas A: PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats. Neurosci Lett 2005, 379:59–62.

    Article  PubMed  CAS  Google Scholar 

  29. Melis MR, Succu S, Sanna F, et al.: PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain. Eur J Neurosci 2006, 24:2021–2030.

    Article  PubMed  Google Scholar 

  30. Kolasa T, Matulenko MA, Hakeem AA, et al.: 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction. J Med Chem 2006, 49:5093–5109.

    Article  PubMed  CAS  Google Scholar 

  31. Argiolas A, Melis MR, Murgia S, Schioth HB: ACTH-and alpha-MSH-induced grooming, stretching, yawning and penile erection in male rats: site of action in the brain and role of melanocortin receptors. Brain Res Bull 2000, 51:425–431.

    Article  PubMed  CAS  Google Scholar 

  32. Giuliano F: Control of penile erection by the melanocortinergic system: experimental evidences and therapeutic perspectives. J Androl 2004, 25:683–691.

    PubMed  Google Scholar 

  33. Mizusawa H, Hedlund P, Andersson KE: Alpha-Melanocyte stimulating hormone and oxytocin induced penile erections, and intracavernous pressure increases in the rat. J Urol 2002, 167:757–760.

    Article  PubMed  CAS  Google Scholar 

  34. Martin WJ, McGowan E, Cashen DE, et al.: Activation of melanocortin MC(4) receptors Increases erectile activity in rats ex copula. Eur J Pharmacol 2002, 454:71–79.

    Article  PubMed  CAS  Google Scholar 

  35. Hadley ME, Dorr RT: Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides 2006, 27:921–930.

    Article  PubMed  CAS  Google Scholar 

  36. Wessells H, Hruby VJ, Hackett J, et al.: MT-II induces penile erection via brain and spinal mechanisms. Ann N Y Acad Sci 2003, 994:90–95.

    Article  PubMed  CAS  Google Scholar 

  37. Wessells H, Hruby VJ, Hackett J, et al.: Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal melanocortin receptors. Neuroscience 2003, 118:755–762.

    Article  PubMed  CAS  Google Scholar 

  38. Giuliano F, Rossler AS, Clement P, et al.: The use of telemetry technology to test the proerectile effect of melanotan-II (MT-II) in conscious rats. Eur Urol 2005, 48:145–151.

    Article  PubMed  CAS  Google Scholar 

  39. Giuliano F, Clement P, Droupy S, et al.: Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat. Neuroscience 2006, 138:293–301.

    Article  PubMed  CAS  Google Scholar 

  40. Herbert GW, Shadiack AM, Koegler FH, Cameron LJ: Effects of PT-141 on erectile dysfunction in adult male sprauge-dawley rats and rhesus macaques [abstract]. J Urol 2001, 165:229.

    Google Scholar 

  41. van der Kraan M, Tatro JB, Entwistle ML, et al.: Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. Brain Res Mol Brain Res 1999, 63:276–286.

    Article  PubMed  Google Scholar 

  42. Vergoni AV, Bertolini A, Mutulis F, et al.: Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioural effects in rats. Eur J Pharmacol 1998, 362:95–101.

    Article  PubMed  CAS  Google Scholar 

  43. Vemulapalli R, Kurowski S, Salisbury B, et al.: Activation of central melanocortin receptors by MT-II increases cavernosal pressure in rabbits by the neuronal release of NO. Br J Pharmacol 2001, 134:1705–1710.

    Article  PubMed  CAS  Google Scholar 

  44. Pavone C, Curto F, Anello G, et al.: Prospective, randomized, crossover comparison of sublingual apomorphine (3 mg) with oral sildenafil (50 mg) for male erectile dysfunction. J Urol 2004, 172:2347–2349.

    Article  PubMed  CAS  Google Scholar 

  45. Perimenis P, Markou S, Gyftopoulos K, et al.: Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study. Andrologia 2004, 36(3):106–110.

    Article  PubMed  CAS  Google Scholar 

  46. Eardley I, Wright P, MacDonagh R, et al.: An open-label, randomized, flexible dose, crossover study to assess the comparative efficacy and safety of sildenafil citrate and apomorphine hydrochloride in men with erectile dysfunction. BJU Int 2004, 93:1271–1275.

    Article  PubMed  CAS  Google Scholar 

  47. Yamaguchi Y, Kobayashi H: Effects of apomorphine, physostigmine and vasoactive intestinal peptide on penile erection and yawning in diabetic rats. Eur J Pharmacol 1994, 254:91–96.

    Article  PubMed  CAS  Google Scholar 

  48. Elabbady A, Hassouna MM, Elhilali M: Apomorphine versus mating behavior in testing erectile capabilities of diabetic rats. Urology 1995, 45:715–719.

    Article  PubMed  CAS  Google Scholar 

  49. Hannan JL, Smallegange C, Hale TM, et al.: Impact of antihypertensive treatments on erectile responses in aging spontaneously hypertensive rats. J Hypertens 24:159–168.

  50. Gontero P, D’Antonio R, Pretti G, et al.: Clinical efficacy of Apomorphine SL in erectile dysfunction of diabetic men. Int J Impot Res 2005, 17:80–85.

    Article  PubMed  CAS  Google Scholar 

  51. Perimenis P, Markou S, Gyftopoulos K, et al.: Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study. Andrologia 2004, 36:106–110.

    Article  PubMed  CAS  Google Scholar 

  52. Park JY, Son H, Kim SW, Paick JS: Potentiation of apomorphine effect on sildenafil-induced penile erection in conscious rabbits. Asian J Androl 2004, 6:205–209.

    PubMed  CAS  Google Scholar 

  53. Mizusawa H, Hedlund P, Sjunnesson J, et al.: Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist. Br J Pharmacol 2002, 136:701–708.

    Article  PubMed  CAS  Google Scholar 

  54. Mizusawa H, Hedlund P, Brioni JD, et al.: Nitric oxide independent activation of guanylate cyclase by YC-1 causes erectile responses in the rat. J Urol 2002, 167:2276–2281.

    Article  PubMed  CAS  Google Scholar 

  55. Lammers PI, Rubio-Aurioles E, Castell R, et al.: Combination therapy for erectile dysfunction: a randomized, double blind, unblinded active-controlled, cross-over study of the pharmacodynamics and safety of combined oral formulations of apomorphine hydrochloride, phentolamine mesylate and papaverine hydrochloride in men with moderate to severe erectile dysfunction. Int J Impot Res 2002, 14:54–59.

    Article  PubMed  CAS  Google Scholar 

  56. Diamond LE, Earle DC, Garcia WD, Spana C: Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology 2005, 65:755–759.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Lund University Hospital, S-221 85, Lund, Sweden

    Petter Hedlund MD, PhD

Authors
  1. Petter Hedlund MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petter Hedlund MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hedlund, P. Centrally acting drugs for erectile dysfunction: Do they have a future?. Curr sex health rep 4, 71–76 (2007). https://doi.org/10.1007/s11930-007-0005-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11930-007-0005-2

Keywords

Search

Navigation