Preclinical Effects of Melanocortins in Male Sexual Dysfunction

Home , Bremelanotide, Melanotan II

International Journal of Impotence Research (2008) 20, S11–S16 & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00 www.nature.com/ijir Preclinical effects of melanocortins in male sexual dysfunction

AM Shadiack1 and S Althof2

1Locus Pharmaceuticals, Blue Bell, PA, USA and 2The Center for Marital and Sexual Health of South Florida, West Palm Beach, FL, USA

The neurobiology of sexual behavior involves the interrelationships between sex steroids and neurotransmitters that result in both central nervous system (CNS) effects and effects in the genitalia. Tools such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scanning can help determine what areas of the brain are activated under sexual stimulation. Our understanding of the role of various neurotransmitters, neurosteroids and other CNS-acting compounds is improving. The role of CNS-acting compounds such as dopamine agonists in the treatment of male sexual dysfunction is under active investigation. Melanocortins have CNS and peripheral roles in a wide variety of bodily functions. The melanocortin agonist bremelanotide appears to act in the CNS to promote erections in preclinical models, and may also stimulate behaviors that facilitate sexual activity beyond their erectogenic effects. International Journal of Impotence Research (2008) 20, S11–S16; doi:10.1038/ijir.2008.17

Keywords: erectile dysfunction; neuroanatomy; neurophysiology; CNS-acting agents; melanocortins; bremelanotide

Introduction Neuroanatomy of male sexual response

The neurobiology of sexual behavior involves the Sex and the brain interrelationships between sex steroids and neuro- Sexual arousal can now be studied with such transmitters that result in both central nervous sophisticated tools as PET (positron emission system (CNS) effects and effects in the genitalia. tomography) and fMRI (functional magnetic reso- Despite the advances made over the past 20 years in nance imaging) scanning to determine what areas of male sexual dysfunction, we are just beginning to the brain are activated under sexual stimulation.1 understand the incredibly intricate interplay Using these techniques, when sexually stimulated, between neurotransmitters and neurosteroids in the activation of the right subinsular/insula region the CNS and periphery as initiators and/or facili- including the claustrum has been demonstrated tators of the sexual response cycle. using both fMRI and PET scanning techniques.2 When discussing male sexual response, three Other brain regions that have been reported to be major areas are usually considered. The first is activated during visual sexual stimuli include the libido, or desire to engage in sexual behaviors. The right middle gyrus, right temporal gyrus, left second is the erectile response, which is the caudate and putamen, bilateral cingulate gyri, right ultimate end-organ manifestation of sexual sensimotor and pre-motor regions.1 Other studies motivation and arousal. Although interrelated, one have shown activation of the cerebellum in response can have arousal without desire and vice versa. The to visual erotic stimuli as well as viewing pictures of third major area of male sexuality is disorders of sexual partners. In addition, PET scan studies have orgasm and ejaculation; however, this will not be shown differences in brain activation among men covered in this review. with normal compared with hypoactive sexual responses when viewing sexual stimuli of varying grades of intensity.3 In men with hypoactive sexual desire disorder, prolonged activation of the medial orbitofrontal cortex, which is involved in general inhibition of motivation, was seen. Men also appear to have different brain activation patterns than women in response to sexual stimuli.4 Correspondence: Dr AM Shadiack, Locus Pharmaceuti- In this study, men displayed greater activation of the cals, 4 Valley Square, 512 Township Line Road, Blue Bell, hypothalamus and amygdala compared with women PA 19422, USA. overall in response to visual stimuli. Women who E-mail: [email protected] reported increased sexual arousal after being Effects of melanocortins in male sexual dysfunction AM Shadiack and S Althof S12 presented the erotic visual stimuli showed similar Parasympathetic postganglionic fibers reach the activation of the hypothalamus and amygdala. This penis via the cavernous nerve. Penile erection is may explain why men have a greater sensitivity to seen when sacral cord, sacral roots, sacral nerves, visual sexual stimuli than women. the pelvic nerve or the cavernous nerve is stimu- In the supraspinal area, studies in animals have lated. identified the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus and hippocampus as important centers for sexual function and penile erection.5,6 In particular, the Neurobiology of sexual response MPOA appears to be critical for male sexual behavior in all vertebrate species.7 The nuclei of The central neurochemistry mediating sexual beha- hypothalamic neurons contain several neurotrans- viors include biogenic amines (dopamine, seroto- mitters that may be involved in penile erection, nin, noradrenaline and adrenaline) and peptides although the precise role and sequence of their (oxytocin, prolactin and melanocortins) that affect activity remains to be elucidated. the spinal network control of penile erection.10 In addition, steroid hormones facilitate the sexual response process, most likely by facilitating changes in the release or effectiveness of one or more Neural innervation of the penis 7 Input from the brain is relayed through descending neurotransmitters. spinal pathways to the penis through lumbar Dopaminergic drugs have long been known to sympathetic and sacral parasympathetic outflows.8 facilitate masculine sexual behavior. Although the Basal antierectile tone in the flaccid state is D2 receptor family seems to be responsible for most of the behavioral effects of dopamine, D1 receptors mediated by sympathetic innervation of the pelvis, 11 issuing from spinal segments T11 to L2.9 also may play a role in sexual response. Rodent The dorsolumbar spinal cord is the source of studies have concluded that dopamine is involved sympathetic pro-erectile pathways.10 Preganglionic in anticipatory rather than in consummatory moti- sympathetic fibers reach the penis via the lumbar vational sexual responses. Quail models have proposed that dopamine activates a-2-noradrenergic splanchnic nerves or the paravertebral sympathetic 12 chain, which relay ganglionic neurons in the receptors in the MPOA. Peripheral dopamine D1 hypogastric plexus or in the paravertebral sympa- and D2 receptors have been identified in both rat and human seminal vesicles; however, the role of thetic chain ganglia. Sympathetic postganglionic 13 axons reach the penis through the hypogastric peripheral dopamine has not been established. In nerve, the paravertebral sympathetic chain and the a study of human volunteers, a single dose of levodopa facilitated somatic motor responses to paravertebral sympathetic chain via the pudendal 14 nerve to the penis (Figure 1). Axons from pregan- sexual stimuli among men, but not women. glionic parasympathetic neurons emanate from Parkinson disease patients treated with dopaminer- sacral parasympathetic nuclei, establishing synapses gic substances such as apomorphine, levodopa or in the pelvic plexus via the pelvic nerve. bromocriptine report the occurrence of erections and increased libido or an improved sexual interest. Serotonin appears to inhibit sexual function; however, this effect is most likely subtype specific. An increase in the concentration of the primary serotonin metabolite 5HIAA in the nucleus accum- bens and the MPOA after ejaculation suggests that serotonin is involved in sexual satiety.15 Inhibition of the 5-HT2C receptor results in decreased sexual behavior in rats and retarded ejaculation in man, whereas 5-HT1A inhibition does not produce similar 16 effects. However, 5-HT1A receptor effects may depend upon location of the receptor in the brain as well as the level of activation (that is, dose effect). In rats, increasing serotonin by microinjection of selective serotonin reuptake inhibitor into the lateral Figure 1 Extrinsic innervation of the male genital tract. B, bladder; CN, cavernous nerve; CP, celiac plexus; DPN, dorsal hypothalamic area increased the latency time of penile nerve; HN, hypogastric nerve; IMG, inferior mesenteric onset of copulation as well as the latency to the first ganglion; ISN, inferior spermatic nerve; P, prostate; PN, pelvic ejaculation.7 nerve; PudN, pudendal nerve; SC, paravertebral sympathetic Other CNS-acting peptides also play a role in chain; SSN, superior spermatic nerve; SV, seminal vesicles; VD, sexual response. Prolactin influences the sexual vas deferens. L, lumbar; T, thoracic; and S, sacral segments of the 17 spinal cord.10 From Giuliano F et al.10 with permission from excitement phase. Hyperprolactinemia in men has Elsevier. been associated with a variety of effects, such as loss

International Journal of Impotence Research Effects of melanocortins in male sexual dysfunction AM Shadiack and S Althof S13 of libido, erectile dysfunction, gynecomastia, re- leads to an increased release of dopamine in both duced seminal volume and ejaculatory dysfunction. basal and sexual contexts, ultimately resulting in Dopamine lowers prolactin levels and dopaminergic greater response to sexual stimuli. agents are the treatment of choice for prolactino- mas.18 Oxytocin is present in the paraventricular and supraoptic nuclei of the hypothalamus.19 Central oxytocinergic neurons project to other areas Melanocortins of the brain and the spinal cord, where they are thought to influence memory, learning, sexual Melanocortins are a group of small protein mole- behaviors—including penile erection and the post- cules that share the same precursor molecule, POMC orgasmic feeling of sexual satiety—as well as (proopiomelanocortin).25 These peptides include behaviors such as social attachment and bonding.20 ACTH (adrenocorticotropic hormone), the melano- The interaction between steroids and neurotrans- cyte-stimulating hormones (a-MSH, b-MSH and mitters in the CNS is still an area of active g-MSH), b- and g-lipotropin, and b-endorphin. In investigation.21 Steroid hormones easily cross the the CNS, melanocortins may act as neurohormones blood–brain barrier, where extensive steroid meta- or neurotransmitters, regulating numerous functions bolism occurs. Neurosteroids, whether originating within the neuronal systems in which they are from outside the CNS or synthesized de novo in the synthesized and secreted.26 It has been proposed brain, modulate a wide range of neurotransmitters in that melanocortins, oxytocin and dopamine use a the brain, including GABA (g-aminobutyric acid), common pathway in the CNS that involves activa- NMDA (N-methyl-d-aspartate), and nicotinic, mus- tion of NO to control erection.27 carinic, serotonin (5-HT3), kainate, glycine and Five melanocortin receptors have been identified sigma receptors. that are associated with such diverse biological Nitric oxide (NO) is the primary signaling me- functions as skin pigmentation, food intake, the chanism for penile erection. As reviewed elsewhere sleep–wake cycle and sexual response. Investiga- in this supplement, the endothelium of the penile tions into the role of the melanocortin system on vasculature is a major source of NO, and distur- sexual response has focused on the melanocortin 3 bances in endothelial function have been shown to (MC3R) and melanocortin 4 (MC4R) receptors in the be associated with erectile dysfunction of varying CNS. There is abundant expression of both MC3R degrees of severity. and MC4R in the brain and in peripheral genital Neuronal NO also plays an important role in sensory outputs (Figure 2).27 However, MC4R has erectile function. nNOS (neuronal NO synthase) is been shown to modulate erectile function and found in cavernous nerves and their terminal end- sexual behavior, whereas MC3R has not been shown ings within the corpora cavernosa, as well as in the to have a pro-erectile effect.28 MC4R is expressed in nerve plexuses in the adventitia of the deep the rat and human penis, as well as in rat spinal cavernous arteries and the branches of the dorsal cord, hypothalamus, brainstem and pelvic ganglion, penile nerves.22 In the CNS, the PVN contains a but not in rat corpus cavernosal smooth muscle significant amount of NOS.16 Apomorphine and cells. In mice, administration of an MC4R agonist other dopamine agonists have been shown to increased copulation, whereas knockout mice lack- increase NOS activity within oxytocinergic neurons ing the gene encoding for the receptor showed in the PVN, and NO donors such as nitroglycerin or decreased copulatory behavior. nitroprusside induce erections when injected into the PVN. NO also promotes the release of dopamine in the MPOA. Microinjection of an NOS inhibitor into the MPOA of sexually naive rats inhibited their Melanocortins and erection ability to copulate, suggesting that NO may play Preclinical work conducted indicate that melano- both a central and a peripheral role in sexual cortins promote erection primarily through activity response.7 in the CNS. Both ACTH and a-MSH injected into the In the CNS, steroids such as androgens, estrogens hypothalamic periventricular region of the third and progestins interface with neurotransmitters, ventricle of male rats resulted in increased levels of principally dopamine, to facilitate copulatory beha- penile erection, as well as stretching, yawning and viors.23 In both men and women, this interplay grooming.29 However, neither caused those effects occurs simultaneously in the brain and periphery, when injected into the preoptic area, the caudate changing the person’s desire for sexual activity as nucleus or the CA1 field of the hippocampus. well as enhancing physiological readiness for sex. In a different rat model, 10 min after intracerebro- In rat studies, testosterone was found to promote ventricular administration of a-MSH, there was a increased dopamine release in the MPOA in 10-fold increase in the frequency of penile erec- response to the presence of a female behind a clear tions.30 Increases in erection frequencies were seen barrier.24 Testosterone also appears to upregulate by injecting both ACTH and a-MSH directly into NOS activity in male rats. Increased NO production PVN of the hypothalamus. Blocking the MC4R with

International Journal of Impotence Research Effects of melanocortins in male sexual dysfunction AM Shadiack and S Althof S14 melanocortin receptor-binding region, had no effect on strips of penile tissue from rabbits subjected to an electrical field, but intravenous injections resulted in increased cavernosal pressures.31 The effects of MT-II were abolished by severing the pudendal nerve or by administering L-NAME (NG- nitro-L-arginine methyl ester), an inhibitor of NOS. The data suggest that MT-II effects on erection are cause by activation of central melanocortin receptors resulting in neuronal release of NO. Intrathecal delivery of MT-II to the lumbosacral spinal cord of anesthetized rats was more efficacious in inducing erections than intracerebroventricular or intravenous administration.32 These investigations were among the first to show distal spinal cord involve- ment in the pro-erectile function of melanocortins.

Bremelanotide preclinical investigations Bremelanotide (formerly known as PT-141) is a synthetic analogue of a-MSH, which is an agonist of the MC4R.33 Bremelanotide shows about double the affinity for the MC4R as for the MC3R in cells containing cloned human melanocortin receptors. In preclinical experiments, central doses of bremelanotide delivered into the right lateral ventricle show consistent initiation of spontaneous penile erections in adult male rats (Figure 3).34 In addition, administration of bremelanotide either intrave- Figure 2 Melanocortin 3 (MC3R) and melanocortin 4 (MC4R) nously or intranasally also resulted in spontaneous receptors and the organization of the central and peripheral erections. The frequency of erections increased in a nervous systems involved in the control of erectile dysfunction. DCN, dorsal column nucleus; IML, intermediolateral cell column; dose-dependent manner (Figure 4). In addition, with MeA, medial amygdala; MPOA, medial preoptic area; PAG, repeat doses of bremelanotide, spontaneous erec- periaqueductal gray; PVN, paraventricular nucleus; SPN, sympa- tions continue to be produced without evidence of thetic preganglionic neurons; NPGI, nucleus paragigantocellu- tachyphylaxis. Repeat dosing also results in a laris.27 From Giuliano F27 with permission from the Journal of Andrology. reduction in the time to first erection (latency). Administering L-NAME (an inhibitor of NOS) blocked the pro-erectile effects of bremelanotide, suggesting that NO is involved in this mechanism (Figure 5). To assess the degree of the extent and distribution of neuronal activation, a c-Fos immunoreactivity assay was used.33 Immunoreactivity after systemic administration of efficacious doses of bremelanotide was seen in the PVN and the supraoptic nucleus of the hypothalamus. In addition, an experiment using pseudorabies virus injected into the corpora cavernosa was used to determine associations between the hypothalamus and nerve endings in the penis associated with the erectogenic activity of bremelanotide. Pseudorabies virus was detected in the PVN Figure 3 Increase in the number of penile erections per rat in the 90-min observation period. Rats were dosed intracerebroventri- after a 4- or 5-day wait for retrograde trans-synaptic cularly (ICV) with saline or bremelanotide (BRE). PE, penile transport of the virus to the spinal cord and then the erection. brain. The neuronal activation studies and the pseudorabies experiment suggest that bremelanotide HS014, a non-selective MC4R antagonist, did not acts in the hypothalamus by activating MC3R and/or alter these responses. MC4R. Melanotan-II (MT-II), a cyclic heptapeptide Preclinical experiments in female rats suggest that containing amino acids representing the core bremelanotide may not merely be pro-erectile as in

International Journal of Impotence Research Effects of melanocortins in male sexual dysfunction AM Shadiack and S Althof S15

Figure 4 Frequency of penile erections in rats dosed (a) intravenously and (b) intranasally with bremelanotide (BRE). Mean number of erections per rat increased in a dose-dependent fashion.34

research, such agents may give us options for treatment of those with sexual desire or arousal disorders that are not amenable to therapy with erectogenic agents that work primarily in the vasculature, such as the PDE-5 inhibitors or the prostacyclins. CNS-acting agents may also provide additional pathways that will facilitate or augment other treatment modalities. Finally, CNS-acting agents may prove to be not merely erectogenic in men, but also improve perceptions of psychological pro-sexual correlates such as vitality and youthfulness. As our current treatment options for loss of libido or hypoactive sexual desire disorder in men are inadequate, this Figure 5 Nitric oxide synthase (NOS) inhibitor NG-nitro- research provides new directions that may result in L-arginine methyl ester (L-NAME) reduces mean number of greater improvements in our ability to deal with a erections per rat following dosing with bremelanotide. Eight animals per group were dosed intravenously with 100 ml of saline much wider range of male sexual dysfunction. À1 or L-NAME followed immediately by 100 ml of saline or 3 mgkg bremelanotide.34 PE, penile erection. Acknowledgments male rats, but may also facilitate behavioral changes This work was supported by a grant from Palatin that support sexual activity.35 Female rats who were Technologies, Inc. Editorial support for the devel- given bremelanotide exhibited behaviors associated opment of this paper was provided by Kevin Kehres. with increased proceptivity or motivation to copulation compared with those given a placebo. In this experiment, the rats were placed in specially Disclosure designed cages where the female rat was allowed to set the pace of sexual activity. It was up to the Dr Shadiack was employed by Palatin until 28 female rats to initiate sexual contact with the male September 2007. She holds stock in Palatin and rats. The increase in proceptive or solicitation several patents, and has served as an expert witness behaviors was not due to any general stimulatory for Palatin after leaving the company. Dr Althof is an effect of bremelanotide or accompanied by an effect advisory board member consultant and principal on receptive behaviors such as lordosis. investigator for Palatin. He also serves as a consultant, investigator, advisory board member and/or speakers bureau member for Auxilium, Boehringer Ingelheim, BioSante, Johnson & Johnson, Lilly/ Discussion ICOS, Pfizer, Palatin and Plethora.

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