Abstract: Sildenafil became a blockbuster treatment of erectile dysfunction almost overnight, with sales reportedly totaling $1.5 billion in 2001. Despite the success of sildenafil and improvements that are expected with the development of second-generation PDE5 inhibitors, this approach remains unsuitable for 30-50% of patients due to the severity of disease or to contra-indications. A sizable market therefore remains for the treatment of erectile dysfunction; however, of greater commercial significance is perhaps the female sexual dysfunction market. According to the much-quoted JAMA article published in 1999, more American women (43%; about 40 million) than men (31%) experience some form of sexual disorder. Female sexual dysfunction represents a family of conditions that have few pharmacological therapies. Of interest, and in contrast to males, the distribution of female dysfunctions is fairly even among women ranging from 18 to 59 years of age. Approximately 20% of women with female sexual dysfunction suffer arousal disorder characterized by either a failure of vaginal engorgement/lubrication or an altered appraisal of arousal, and it has been suggested that treatments of female arousal disorder represent a market of similar size to that of erectile dysfunction. Female arousal disorder and moderate to severe erectile dysfunction thus represent indications with blockbuster potential. Due to the similarities between the corpus cavernosum and the clitoris with respect to both structure and innervation, a number of pharmacological targets may be appropriate for both indications. In August, 2002, LeadDiscovery published a state of the art review of sexual dysfunction targets and the pharmaceutical activity surrounding these targets (click here to access). Here we focus on the involvement of adrenoceptors in male and female sexual physiology, and in the pathophysiology of erectile dysfunction and female arousal disorder. The adrenoceptor antagonist, phentolamine has been launched for the treatment of erectile dysfunction and is in clinical development for the treatment of female arousal disorder. This report analyses the development of MDI's novel adrenoceptor antagonist, HMP-12 which is a more potent antagonist of corpus cavernosal contraction than phentolamine and is also able to stimulate vaginal blood flow. We conclude that although adrenoceptor antagonists are unlikely to replace PDE5 inhibitors as treatments of mild erectile dysfunction, such molecules may provide a valuable adjunct to PDE5 inhibitors (or indeed apomorphine) in treating the 50% of patients with moderate to severe disease that are poorly responsive to sildenafil monotherapy. Perhaps more important, adrenoceptor antagonists stand to become the first non-HRT treatment of female arousal disorder in post-menopausal women, and maybe in addition a valuable approach to pre-menopausal women with sexual dysfunctions. Drug development analysis shows that although a large number of adrenoceptor antagonists have been developed few of these are indicated for erectile dysfunction or female arousal disorder, due in part to the selectivity of most of this products to a1 or a2 receptors suggesting that novel mixed adrenoceptor antagonists may be relatively free of competition. HMP-12 therefore offers excellent therapeutic and commercial prospects and MDI are now seeking partners to optimize the development of this potential.

Male sexual dysfunction: Penile erection and detumescence (defined as "subsidence from a swollen state") are hemodynamic events that are regulated by corporal smooth muscle relaxation and contraction, respectively. The corpus cavernosum and the corpus spongiosum are comprised of lacunar spaces lined with vascular smooth muscle. Arteries that supply the penis finish in a capillary network, the branches of which open directly into the cavernous spaces. In the flaccid state, a dominant sympathetic influence prevails, and arterial and corporal smooth muscle are contracted; as a result, only a minimal amount of blood flows through the cavernous artery into the lacunar (latticework-like) spaces. In response to sexual stimulation, parasympathetic activity increases, resulting in a decrease in peripheral resistance due to vasodilation and increased blood flow through the cavernous and helicine arteries. Relaxation of the trabecular smooth muscle surrounding the corpus cavernosum causes increased compliance of the lacunar spaces; increased blood volume and compression of the relaxed trabecular smooth muscle against the outermost tunica albuginea lead to a reduction in the venous outflow, referred to as the veno-occlusive mechanism. A rigid erection occurs and blood flow through the cavernous artery ceases. Detumescence results when elevated sympathetic activity increases the tone of the helicine arteries and contraction of trabecular smooth muscle occurs. This allows venous outflow to be re-established. In addition to the muscles of the corpus cavernosum, the striated perineal muscles at the base of the penis, known as the ischiocavernosus and bulbospongiosus muscles, also appear to be of importance in penile rigidity. In early studies, the penile tumescence, penile rigidity, and electromyographic activities of perineal muscles were reported to increase simultaneously (Lavoisier et al, 1988).

ED, previously and more pejoratively known as impotence, is defined as the inability to attain or sustain an erection satisfactory for coitus. ED is rarely a primary condition (ie. the man has never been able to attain or sustain erections), and when it is, it is almost always due to psychological factors (sexual guilt, fear of intimacy, depression, severe anxiety). Secondary ED is much more common, and occurs when a man who previously could attain and sustain erections no longer can. More than 90% of these cases are organic in nature. The major cause of ED is vascular, although complications of surgical prostatic resection, hormonal disorders, drug use, and neurological disorders all contribute to the etiology of ED. Transient ED arising for any reason may lead to secondary psychological difficulties that compound the problem. The major types of vascular problems that can result in ED are arterial insufficiency, inadequate impedance of venous outflow (venous leaks), or a combination of both. With age and underlying diseases (eg. atherosclerosis, hypertension), dilation of arterial blood vessels and smooth muscle relaxation decrease, and flow becomes impeded, diminishing the amount of blood entering the penis. Diseases that accelerate atherosclerosis (eg. diabetes, smoking, hypertension) therefore increase the prevalence of ED, and indeed ED can be taken as an indication of cardiovascular disease. As ED becomes more long-term, treatment becomes more difficult, partly due to an additional component of the disease coming into play, namely ischemia. Prolonged ischemia results in a loss of penile muscle mass and an increase in fibrosis. In contrast to arterial insufficiency, venous leaks make it difficult for blood to remain in the penis during erection, and therefore also contribute to ED. Finally, as mentioned above, the perineal muscle also contributes to erectile rigidity, and indeed a sub-population of patients that do not fully respond to pharmacological treatments of ED attain satisfactory rigidity if the perineal muscles are simultaneously stimulated, suggesting a possible role for these muscles in ED (Derouet et al, 1998). Despite these findings, few studies have focussed on the modulation or pathophysiological role of the perineal muscles.

In contrast to ED, priapism is defined as painful, persistent, and abnormal erections, unaccompanied by sexual desire or excitation. The mechanisms of priapism are poorly understood but probably involve complex vascular and neurological abnormalities. Pelvic vascular thrombosis is most often incriminated. Priapism may be secondary to prolonged sexual activity, to leukemia, sickle cell disease or trait, or other blood dyscrasias, to pelvic hematoma or neoplasm, to cerebrospinal disease (eg. syphilis, tumors), or to genital infection and inflammation (eg. prostatitis, urethritis, cystitis), especially if complicated by a bladder calculus. Of direct relevance to this report, several therapeutic strategies for the treatment of ED may produce priapism, including various injection therapies, and especially that of PGE1.

Interacting aspects of FSD (after Phillips NA. The clinical evaluation of dyspareunia. Int J Impot Res 1998;10(suppl 2):S117-20.)

FSD can be defined as "the persistent impairment of a couple's normal or usual patterns of sexual interest and/or responses". It is a misconception that FSD is a normal consequence of childbirth, aging, or menopause, or is purely psychological. Each of these factors can play a role, as can smoking and related arteriosclerosis, diabetes, and a variety of different medications. Proper sexual functioning in men and women depends on the sexual response cycle, which consists of an anticipatory mental state (sexual motive state or state of desire), effective vasocongestion (erection in men, swelling and lubrication in women), orgasm, and resolution. The sexual response cycle is mediated by a delicately balanced interplay between the sympathetic and parasympathetic nervous systems. Vasocongestion is largely mediated by parasympathetic (cholinergic) outflow; orgasm is predominantly sympathetic (adrenergic). These responses are easily inhibited by cortical influences or by impaired hormonal, neural, or vascular mechanisms. Although the definition of FSD continues to evolve, it currently consists of four recognized components, mirroring the phases of the sexual response cycle, which are recurring in nature and cause personal distress. The American Foundation of Urologic Disease (AFUD) classifies FSD into four types of disorder:

• Decreased sexual desire, or sexual aversion: This is caused by an ongoing lack of sexual fantasies or thoughts. A woman with hypoactive sexual desire disorder does not have a desire for sex and is not interested in the sexual advances of her partner. This may also be called loss of libido. Sexual aversion disorder involves an ongoing severe fear or phobia of any sexual activity with a partner.
• Decreased sexual arousal (FAD): This is experienced by women who would like to have sex, but when they have sex it is not pleasurable. This may be due to decreased sensitivity in the genitals or lack of vaginal lubrication. Decreased sensitivity is frequently related to menopause since reduced estrogen levels cause atrophy of the vaginal smooth muscle with secondary vaginal wall fibrosis and collagen deposition. FAD may also be caused by decreased blood flow to the vagina or clitoris, although this relationship is less clear than for ED. The level of engorgement is not a critical factor for sexual function, as it is for penile erection, and moreover, women complaining of arousal disorder have been reported to show the same increase in vaginal pulse amplitude in response to erotic videos compared to that of control women. Likewise, although post-menopausal women have lower pulse amplitudes than pre-menopausal women, the level of congestion is similar. These points are of importance to the pharmacotherapy of FAD, since increasing blood flow per se may not be sufficient as an end-point, and rather it may be of greater importance to increase the lubrication response to increased blood flow and the subjective/emotional response to physiological arousal (see Basson, 2002 for a full discussion of these concepts). Due to the complexity of FAD, this condition has been sub-divided into
  • Female genital arousal disorder - This is typical for women with multiple sclerosis or autonomic nerve damage who despite becoming emotionally aroused fail to experience a genital response
  • Missed sexual arousal - This occurs when women become engorged but they are not subjectively aroused, and can be further broken down to include dysphoric sexual arousal (when the woman is aware of being aroused but does not like it) and anhedonic sexual arousal (when the woman experiences neither joy nor dysphoria).
• Sexual pain disorders including vaginismus and dyspareunia: Dyspareunia is ongoing pain associated with sexual intercourse. This is distinct from vaginismus, which is defined as an ongoing spasm or tightening of the muscles of the vagina that makes the vagina difficult to enter or penetrate.
• Persistent difficulty in achieving or inability to achieve orgasm: A sub-population of women find it difficult to have an orgasm or find that reaching orgasm takes a long time. Some women describe their orgasms as "muffled" or not as intense as they once were. Other women may not be able to reach orgasm at all. This problem occurs even though sexual stimulation and arousal is unimpaired.

As described in the previous section, penile erection and female arousal are both dependent on vascular congestion which, in turn, is under the control of similar neural pathways in both men and women. Defects in vascular congestion contribute to about 90% of ED cases. Likewise, altered blood flow or resultant lubrication also affects a significant proportion of women with FSD. Hence, understanding the genital smooth muscle contraction and its neural control have led to, and will continue to lead to, improved treatments for male and female sexual dysfunction.

Control of smooth muscle contraction and relaxation Vascular smooth muscle (VSM) in general is characterized by sustained, tonic contractions initiated by mechanical, electrical, and chemical stimuli. Passive stretching of VSM can cause contraction that originates from the smooth muscle itself and is therefore termed a myogenic response. Electrical depolarization of the VSM cell membrane will also elicit contraction, most likely by opening voltage-dependent calcium channels (L-type calcium channels) and causing an increase in the intracellular concentration of calcium. A number of neurotransmitters can also elicit (or inhibit) contraction.

Neural circuitry to the sexual organs

Like most organs, innervation of the sexual organs is hierarchical in organization. The penis receives an autonomic innervation from sympathetic and parasympathetic nuclei located in the spinal cord, which is in turn modulated by afferent information conveyed by somatic and visceral fibers originating from the penis and perigenital area, and by central pathways. In its distal part, the afferent limb of this reflex is constituted by the dorsal nerve of the penis, and the efferent limb by the cavernous nerve. Thus in anesthetized rats spinalized at the T8 level, penile erections can be generated by electrical stimulation of the dorsal nerve (Pescatori et al, 1993). Electrostimulation of the dorsal nerve triggers multi-unit responses in the cavernous nerve that are eliminated by transection of the pelvic nerve in intact or spinally transected rats (Steers et al, 1988). Clinical data also give support to the existence of a spinal reflex controlling penile erection. Penile erections are known to occur in patients with complete spinal cord injury at the thoracolumbar level, which strongly suggests that the spinal cord contains a neural machinery sufficient for generating penile erection (Chapelle et al, 1980). The hypogastric nerves originate in sympathetic autonomic nuclei, located at the thoracolumbar level, and are anti-erectile, whereas the pelvic nerves originating in the parasympathetic nuclei, located at the lumbosacral level, are pro-erectile. Nerves from these two fibers merge in the pelvic plexus to form the cavernous nerves, which enter the corpora cavernosa and corpus spongiosum to effect the neurovascular events during penile erection and detumescence. The generation of penile erection requires the coordinated activation of the parasympathetic nuclei and inactivation of the sympathetic nuclei. Modulation of the spinal reflex by central pathways has long been known to play an important role in the control of erectile function, and in particular, oxytocin-containing nerves originating in the paraventricular nucleus synapse on preganglionic parasympathetic neurons projecting into the corpus cavernosum. The neurocircuitary to the female genitalia is very similar to that of males.

Smooth muscle signal transduction

Through their receptor binding, a variety of neurotransmitters increase the cytosolic calcium concentration, either as a result of calcium entry into the cell cytoplasm through plasma membrane channels, or by release of calcium from internal stores (eg. the sarcoplasmic reticulum, SR). Calcium binds to calmodulin, which activates myosin light chain kinase (MLCK), which in turn phosphorylates myosin light chains (MLCs), thus facilitating cross-bridge formation between the myosin heads and the actin filaments, and hence, smooth muscle contraction. This process is reversed by the activation of smooth muscle myosin phosphatase and by extrusion/sequestration of calcium. There are several signal transduction mechanisms that modulate intracellular calcium concentration and therefore the state of vascular tone. Norepinephrine (NE) acting via a1-adrenoceptors, angiotensin II (AII) acting via AII receptors, and endothelin (ET)-1 acting through ETA receptors can all activate phospholipase C, causing the formation of inositol 1,4,5-trisphosphate (IP3), which then stimulates the SR to release calcium. The formation of diacylglycerol (DAG) also contributes to VSM contraction via protein kinase C activation and the consequent protein phosphorylation. The heterotrimeric-G-protein-coupled pathways either stimulate (via the Gs protein) or inhibit (via the Gi protein) adenylyl cyclase, the enzyme that catalyzes the formation of cAMP, which itself inhibits MLCK, thus causing muscle relaxation. Finally, nitric oxide (NO) activates guanylyl cyclase, causing an increased formation of cGMP, and relaxation. The precise mechanisms by which cGMP relaxes VSM is unclear; however, cGMP can activate a cGMP-dependent protein kinase, inhibit calcium entry into the VSM, activate K+ channels, and decrease IP3.

In addition to the direct control of smooth muscle tone by changes in intracellular calcium levels, an intracellular pathway, Rho-A/Rho kinase, has recently emerged as a modulator of contractile activity. Rho-A is a monomeric GTPase (or small G-protein) that acts as a major upstream component of Ca2+-sensitization. Upon activation, Rho-A binds to the plasma membrane, which sequentially activates Rho kinase and inactivates, through phosphorylation, the regulatory subunit of smooth muscle myosin phosphatase. Pathological activity of Rho-kinase in smooth muscle has been implicated in experimental hypertension (Uehata et al. 1997) and asthma (Chiba et al. 1999), and Rho-kinase inhibition reduces blood pressure of hypertensive rats (Uehata et al. 1997). An ever-increasing body of literature now documents the important role of the Rho/Rho-kinase-myosin phosphatase inhibition pathway in a variety of non-muscle cells, including platelets (Suzuki et al. 1999), and neuronal (Majumdar et al. 1998) and endothelial cells (Vouret-Craviari et al. 1998; Essler et al. 1998). A highly important pathological consequence of inhibition of myosin phosphatase by Rho-kinase is its enhancement of the motility of malignant cells; hence Rho-kinase inhibitors may play a role in reducing metastasis (Itoh et al. 1999).

Therapeutic goals for the control of genital muscle tone

The general goal for pharmacological treatment of ED, and also for a subpopulation of women with FAD, is to decrease arterial and corpus cavernosum tone as well as possibly increasing venous tone. Decreasing arterial tone can either involve the modulation of neural control (ie. increasing inhibitory and/or decreasing excitatory input) or smooth muscle tone (ie. shifting the muscle from a contractile to a relaxatory state).

Vasoconstrictive mechanisms

NO, that is generated both by both nerves and the endothelial cells that cover the trabeculae of the corpus cavernosum and through stimulation of sGC and the generation of cyclic GMP, is thought to play a dominant role in relaxation of smooth muscle in this tissue. The pathophysiological relevance of the cyclic GMP pathway is evidenced by the successful use of PDE5 inhibitors. Other signaling pathways involving VIP/cAMP are also accepted as being operative in relaxation of the corpus cavernosum, but activation of this pathway is insufficient on its own to produce erection, with inhibition of contractile signals also being required. In severe cases of ED, intervention may be required both to stimulate inhibitory pathways and to block excitatory pathways. The contracted (resting) state of the corpus cavernosum smooth muscle is considered to be mediated by release of NE, ET, and angiotensin. Inhibition of these agonists at the receptor level or in their downstream signaling pathways should, like NO stimulation, also lead to a decrease in myosin regulatory light chain phosphorylation and consequent relaxation through decreased cytoplasmic calcium. Here we focus on adrenergic regulation, however readers with an interest in the (patho)physiological role of inhibitory neurotransmitters (eg the nitric oxide pathway, VIP, prostaglandin or adenosine) other vasoconstricitve mechanisms (eg endothelin and angiotensin), or indeed central (dys)regulation of sexual function are referred to our earlier report (click here to access).

a-Adrenoceptors: The adrenoceptor family was first divided into two subtypes, the a- and b-adrenoceptors, as determined by pharmacological studies in isolated tissue (Ahlquist, 1948). A quarter of a century later, the a-adrenoceptors were further subdivided based on their anatomical location, with the a-adrenoceptors located on peripheral sympathetic nerve terminals designated a2-adrenoceptors, and those located post-synaptically designated a1-adrenoceptors (Langer, 1974). This anatomical classification rapidly gave way to the identification of pharmacological differences between the a-adrenoceptors, notably the ability of yohimbine and rauwolscine to act as a2-adrenoceptor antagonists. Subsequent studies using pharmacological and molecular biology techniques have further subdivided the a-adrenoceptor family; three subtypes within each group have now been cloned and pharmacologically characterized. The a1-adrenoceptor subtypes have been classified as the a1A-, a1B- and a1D-adrenoceptors and the a2-adrenoceptors have been classified as the a2A- (a2D- species variation of the human a2A-), a2B- and a2C-adrenoceptors.

The importance of the a-adrenergic neuroeffector system in erectile function has long been recognized (see Andersson & Stief, 2001). Evidence from in vitro and in vivo studies has indicated that adrenergic nerves, a major source of physiologically active NE, innervate the corpus cavernosum. NE is an important neurotransmitter in the control of penile detumescence (Andersson & Wagner, 1995; Christ et al, 1990; Saenz de Tejada et al, 1991) and acts on post-junctional a1- and a2-adrenoceptors, inducing contraction in trabecular smooth muscle and penile vessels. When administered systemically, a-adrenoceptor antagonists facilitate penile erection and produce prolonged erection or priapism (Andersson & Wagner, 1995; Diederichs et al, 1990;Traish et al, 1995). Traish et al (1997) identified a1- and a2-adrenoceptor subtypes in corpus cavernosum smooth muscle using a variety of techniques, including mRNA expression, receptor binding studies and organ bath methodologies. The same authors demonstrated that corpus cavernosum contractility to NE or phenylephrine is dependent on the contributions of more than one a1-adrenoceptors subtype, and, of note, Veronneau-Longueville et al (1998) have reported expression of a1A-, a1B- and a1D-adrenoceptor expression by the rat corpus cavernosum. Furthermore, Traish et al (1997) have also demonstrated expression of post-junctional a2-adrenoceptors in the corpus cavernosum and showed that these receptors are physiologically functional (Traish et al, 1997; Gupta et al, 1998). NE released from adrenergic nerves binds to a1-adrenoceptors, localized on the corpus cavernosum smooth muscle, releasing Ca2+ from intracellular stores and increasing DAG levels. The mechanisms of action of a2-adrenoceptor in the corpus cavernosum are yet to be fully understood. Studies in other vascular systems have shown that a2-adrenoceptor activation inhibits adenylyl cyclase; however, a2-adrenoceptor activation has also been shown to modulate Ca2+ influx and to activate phospholipase C and phospholipase D (MacKinnon et al, 1994). Based on the current state of knowledge, the following consensus model has been proposed regarding presynaptic modulation by NE: NE release from adrenergic nerves binds to the pre-junctional a-2 adrenoceptor on NANC fibers thus inhibiting NO synthesis and release. Blockade by selective a2-adrenoceptor antagonists (e.g. yohimbine or delequamine) enhances NO release, facilitating erection. In addition, NE release from adrenergic nerves binds to the pre-junctional a2-adrenoceptor on the adrenergic nerves and negatively regulates NE release. Blockade of this reaction by selective a2-adrenoceptor antagonists (e.g. yohimbine or delequamine) enhances NE release, limiting the efficacy of such molecules. Based on these concepts for pre-junctional and post-junctional regulation of smooth muscle tone, the most efficacious strategy to reduce adrenergic activity and facilitate penile erection is to combine a1 and a2 adrenergic receptor antagonists. In this case, any enhancement of NE release by presynaptic receptor blockade is of little importance because the a1 receptor antagonist will impede this vasoconstrictor response. This will also enhance the release of NO, which increases smooth muscle relaxation and decreases contraction, resulting in penile erection. Although the majority of information regarding the influence of a-adrenoceptors on erectile function concerns peripheral effects, a body of data does exist supporting the involvement of central adrenoceptors. Chang et al (2001) suggested that a1A/D-, a2B-, and a2C-adrenoceptors in the hippocampus are involved in a negative feedback loop that inhibits erectile activity. The adrenoceptor profile which is optimal for ED remains unknown although the available information has been reviewed by Saenz de Tejada (2000).

Supported by this body of preclinical data, the mixed a1/2-adrenoceptor antagonist phentolamine has been evaluated in a number of clinical trials (see Goldstein, 2001 for a review). In summary, at oral doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration, with 51% and 53% achieving penetration on 75% of attempts. The correction of ED or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. Phentolamine is thus generally accepted as being efficacious for the treatment of ED. When taken orally on a regular basis before sleep, it may be able to prevent ED in men at risk, protecting also minimally and moderately impotent patients from becoming moderately and severely impotent respectively (Hatzichristou et al, 2001). Offering further support to the concept that mixed a1/2-adrenoceptor antagonists may offer a better approach to ED than through the use of more selective antagonists is the relatively limited therapeutic efficacy of yohimbine (a selective a2-adrenoceptor antagonist; for review see Tam et al, 2001) and Ro70-0004 (a selective a1A adrenoceptor antagonist; see Choppin et al, 2001). In summary therefore mixed a1/2-adrenoceptor antagonists are of benefit in the treatment of ED. The mutual interaction between nitrergic and adrenergic innervation is of particular interest. NO is known to reduce the excitatory pro-erectile effects of NE (see above); likewise NE is known to prevent NO release. Thus a combination of a mixed a1/2-adrenoceptor antagonist and molecules such as sildenafil may offer excellent therapeutic opportunities, although the risk of priapism should be evaluated. Furthermore, human penile circumflex veins have been shown to express functional a1- and a2-adrenoceptor subtypes which mediate the contractile response to NE (Kirkeby et al, 1989). There is therefore a risk that blocking these receptors may increase venous leak, and this possibility should thus be assessed.

A small pilot study conducted to determine the effects of oral phentolamine in menopausal women with FSD was reported in 1999 (Rosen et al). Six postmenopausal women with a lack of lubrication and with sexual arousal difficulties received a single dose of oral phentolamine (40 mg) and placebo in a single-blind, dose-escalation design. Phentolamine increased lubrication and pleasurable sensations in the vagina. The drug was well tolerated, overall, with few reports of adverse side effects. Likewise, Rubio-Aurioles et al (2002) demonstrated efficacy, although this was restricted to those women receiving HRT. Finally, a combination of yohimbine and an NO donor has been shown to increase lubrication in post-menopausal women (Meston & Worcel, 2002). Consistent with these studies are reports that the a2 adrenergic agonist clonidine reduces vaginal blood flow (Meston et al, 1997). Thus phentolamine represents one of the most promising targets for the treatment of FAD to date and parallels the situation for PDE5 inhibitors described above.

In the 30% of patients with moderate ED, mono- or multi-modal intracavernosal therapies remain the recommended option. In the 20% of patients with severe ED, the implantation of protheses is usually performed. The development of oral therapies for moderate and severe ED would therefore be of considerable use. One approach to this objective would be to both increase inhibitory neurotransmission through the NO pathway and inhibit excitatory neurotransmission. Mixed adrenergic receptor antagonists such as phentolamine appear to be the most effective approach to inhibiting excitatory pathways, and it is important to note that phentolamine is effective in treating ED, although it has lower efficacy and poorer tolerability that sildenafil (Ugarte & Hurtado-Coll, 1992). This offers good proof of concept for the development of adrenoceptor (especially mixed a1/a2) antagonists for ED. Therefore, although sildenafil may be preferable to phentolamine as a monotherapy, the combined use of both treatments in more severe ED may be indicated. Studies comparing the effects of sildenafil plus phentolamine with the use of either therapy alone are yet to be performed; however, preclinical data shows that the two molecules act in a synergistic fashion (Kim et al, 2000). Thus the development of phentolamine or other adrenoceptor antagonists deserves pharmaceutical attention, although the risk of priaprism associated with such an approach should be considered. Furthermore it is of interest that in the treatment of men with moderate to severe ED a combination of oral phentolamine and apomorphine is as effective as sildenafil and is associated with fewer side-effects (Lammers et al, 2002). Thus phentolamine may be able to capture some of the sildenafil market when used with apomorphine.

Although ED still holds considerable opportunities for the pharmaceutical industry, FSD remains the major unmet market in this therapeutic sector. The level of research and the degree of drug development relating to FSD lags far behind that of ED. Furthermore PDE5 inhibitors have met with less success in women than in men, especially in postmenopausal women. In contrast, HRT has been shown to be of use in post- but not premenopausal women. Since the structure and innervation of the clitoris and the corpus cavernosum share many similarities, the targets developed for ED should be evaluated with respect to FSD. Arising from such studies is the observation that adrenoceptor antagonism appears to be a particularly useful approach to post-menopausal women with FAD, although the target patient group requires further clarification.

Highlighted technology:  HMP-12

Project Profile: MDI's HMP-12 is a mixed adrenoceptor antagonist in development for sexual dysfunction that has been evaluated in collaboration with Drs Traish, Kim, Munarriz and Goldstein at Boston University School of Medicine. Contractile responses have been assessed in organ-bath preparations of isolated rabbit cavernosal tissue strips (see graph to the left). All tissue strips were treated with indomethacin to reduce the vasoactive influences of endogenous prostanoids. In cavernosal tissue strips exposed to increasing concentrations of exogenous NE, HMP-12 (50 nM) significantly attenuates the contractile response (n = 6). In a separate protocol, cavernosa tissue strips were contracted with NE and then challenged with increasing concentrations of HMP-12. HMP-12 causes dose-dependent relaxation of these tissue strips with an estimated EC50 of 0.12 mM (n = 8). Those results indicate that HMP-12 is an effective a-adrenoceptor antagonist in penile corpus cavernosum and provide a rationale for further development of this compound as a potential treatment for male ED.

In addition to showing activity in corpus cavernosum preparations, HMP-12 has been shown, in the female rabbit to increase genital blood flow in response to pelvic nerve stimulation (30 sec trains of square waves with 10 V pulse amplitude, 0.8 msec pulse width and 2 Hz frequency). As shown in the Figure to the right, administration of phentolamine mesylate or HMP-12 produces a dose dependent increase in total hemoglobin levels, as measured using a vaginal plethismograph. No significant changes in systemic blood pressure have been noted for intravaginal administration of phentolamine or HMP-12.

Patent Position: HMP-12 and its chemical series is protected by US60-311/320, filed on August 10, 2001. MDI owns 100% of all rights related to the patent and may enter into an out-license agreement with no reservations.

Disease incidence and market values: The launch of sildenafil revolutionized the ED market overnight. Sales totaling $1.5 billion were reported for 2001. A second PDE5 inhibitor, vardenafil has been predicted to generate peak sales of US $0.85 billion worldwide (Sommer & Engelmann, 2002). According to the much-quoted JAMA article published in 1999, more American women (43%; about 40 million) than men (31%) experience some form of sexual disorder (Laumann et al). FSD represents a family of conditions that have few pharmacological therapies. Of interest, and in contrast to males, the distribution of female dysfunction is fairly even among women ranging from 18 to 59 years of age. MDI analysts predict that, as a treatment for FSD and with successful development and marketing, HMP-12 will achieve blockbuster sales in excess of $1 billion peak year, in agreement with the concept that FSD represents a market of similar size to that of ED.

Drug development databases have also been searched in order to identify companies responsible for the development of treatments for sexual dysfunction, and also those who have in-licensed technology from these companies. These are given below:

Originators: Abbott; Antares Pharma; Ardana; Ardent Pharmaceuticals; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Britannia; Cellegy Pharmaceuticals; Cemorc; CJ Corp; Columbia Laboratories; Cortex Pharmaceuticals; Dong-A; Eisai; Elan; Eli Lilly; Fournier; Fujisawa; Futura Medical; Galen Ltd; GlaxoSmithKline; ICOS; Inspire; Johnson & Johnson; LAM Pharmaceutical; LION bioscience; MacroChem; Merck KGaA; Mitsubishi Pharma; Molecular Design; Nastech; NexMed; NicOx; NitroMed; Novartis; Nycomed Pharma; Ono; OxoN Medica; Palatin Technologies; Pentech Pharmaceuticals; Pfizer; Pharmacia; Purdue Pharma; Schering-Plough; Senetek; Sepracor; Tanabe Seiyaku; Vivus; Watson; Zonagen

Licensees: Abbott; BioSante; Chugai; Dong-A; Douglas; Eli Lilly; Esteve; Ferring; GlaxoSmithKline; Gramon; Icagen; Johnson & Johnson; Lavipharm; Menarini; Mylan Laboratories; Ono; Paladin Labs; Pharmacia; PPD; Procter & Gamble; Recordati; Schering AG; Schering-Plough; Schwarz Pharma; Servier; Stada; Taisho; Takeda; Vernalis; Viatris; Vivus

This report makes the point that adrenoceptor antagonists represent candidates for the treatments for sexual dysfunction. Thus, an analysis of the databases has been performed to identify those molecules currently in development. Retrieved data are given below.