Viagra challenger emerges from research

By Wai Lang Chu

- Last updated on GMT

Related tags: Erectile dysfunction, Dopamine

The next generation of orally-active erectile dysfunction (ED)
drugs took a step closer as researchers isolated a receptor that
could be used as a target of drug treatment without the side
effects associated with the only approved class, headed by Pfizer's
$1.9bn (€1.58bn) product Viagra.

The scientists discovered the molecular pathway, centred on the neurotransmitter dopamine and its receptors while experimenting on rats. Dopamine has already been explored as a target for ED treatment, but enthusiasm has waned because non-selective drugs targeting this neurotransmitter have been held back by side effects.

Now, it appears that compounds which target just one of the five dopamine receptor subtypes could avoid these side effects, and could even have a cleaner toxicity profile than Viagra, which works by blocking the enzyme phosphodiesterase 5 (PDE-5).

The team, at Abbott Laboratories and Lund University in Sweden discovered that stimulation of the D4 dopamine receptor was responsible for erections in rats. D4 receptors have a similar pharmacological profile to the closely related D2 receptors. They are expressed in the brain, predominantly in the medulla, amygdala, midbrain and frontal cortex.

It is the stimulation of the D2 receptors that causes the unwanted side effects associated with the drugs. They all act by affecting blood flow, notably to the penis, but can cause headaches, heartburn and flushing. As a result they should not be taken along with heart drugs such as alpha blockers or nitrates, which is a drawback as many men suffer ED as a result of cardiovascular disease.

A report by Abbott Laboratories, published in this week's Proceedings of the National Academy of Sciences claimed their experimental drug ABT-724 seemed to affect D4 without affecting other dopamine receptors.

The report stated: "The ability of ABT-724 to facilitate penile erection together with the favourable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction."

An Abbott spokeswoman said ABT-724 had passed Phase I safety studies and that the company was seeking to license the compound to another company.

Since Pfizer's Viagra (sildenafil) was approved in 1998, annual global sales have reached $1.9 bn. The product had the oral ED market to itself until last year, when two rivals entered the market, namely Levitra (vardenafil) from GlaxoSmithKline (GSK) and Bayer and Cialis (tadalafil) from Eli Lilly and Icos. Both these drugs have the same mechanism of action as Viagra,

At the European Association for Urology meeting in Vienna, Cialis claimed it had overtaken Levitra in the USA in terms of new prescriptions written (18 per cent versus 15 per cent).

Bayer and GSK commented that by the end of 2003, market share in the US was 10 per cent based on sales of 7m tablets compared to 2m for Cialis. GSK reported that Levitra sales were £37m (€55.4m) in 2003, while Bayer said the drug brought in €144m.

However, the firms are still jostling for position. Just this week, Lilly ICOS said that - in the three weeks prior to the announcement - Cialis had overtaken Levitra in the US in terms of new prescriptions written. The company reported Cialis sales of around $200m in 2003.

Related topics: Preclinical Research

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