Pherin has discovered human nasal chemosensory substances, termed vomeropherins, and has gathered a large body of human data that indicate these compounds can have significant applications as pharmaceuticals. Vomeropherins are not ingested or injected, but rather are self-administered by the patient with a metered nasal spray, or nasal aerosol device. Once they have been administered intranasally, vomeropherins bind to peripheral chemosensory receptors in the nasal passages.

Vomeropherins affect key areas of the brain. These compounds do not need to circulate in the bloodstream in order to produce an effect. Instead, they initiate neural impulses directly in nasal sensory receptors. These impulses are transmitted by specific pathways that directly and rapidly affect brain function.

Human Nasal Chemosensory Receptor Systems

Pherin research has shown that nasal receptors for vomeropherins are physically and physiologically distinct from olfactory receptors and that certain chemical compounds activate vomeropherin receptors. In humans, receptors for vomeropherins are concentrated laterally in the mucosal lining of the nasal septum. In 1959, certain naturally occurring biochemicals were described as insect pheromones, i.e. chemicals produced and secreted by an animal that serve as a stimulus to other individuals of the same species for one or more behavioral responses (Karlson, P. and Luscher, M., 1959). In 1976, the first neuroendocrine response elicited by pheromones was proposed in mammals (Johns, M.A. et al, 1978). At the beginning of the 1990's, Dr Louis Monti and colleagues established a group of distinct nasal chemosensory receptor sites in humans as the functional nasal receptors for human pheromones and vomeropherins.

Vomeropherins are detected in a manner that is comparable in many respects to the way in which olfactory receptors detect odors. Terrestrial mammals detect odors via distinct receptors that are exposed constantly to inhaled air. When an odorous molecule contacts its specific receptor, an olfactory signal is transmitted to the olfactory cortex of the brain, which leads to interpretation of this signal as a perceived odor.

Human vomeropherin receptors are also exposed to air inhaled through the nose. Pathways into the brain are stimulated when a vomeropherin contacts its receptor in the nose. However, vomeropherin information may be transmitted to the brain without eliciting any perceptible conscious sensation (i.e., most vomeropherins are odorless).

Binding of a vomeropherin to its receptor triggers chemosignals that are transmitted to the hypothalamic and limbic regions of the brain. The hypothalamus acts as the link between the nervous system and the endocrine system. These brain areas control vital regulatory and behavioral functions, such as

• the hormonal system
• the fight or flight response
• mood
• sexual behavior
• body temperature
• appetite and sugar and fat metabolism
• water and electrolyte balance

As a consequence of binding to receptors, vomeropherins are can influence the regulatory functions exerted by the hypothalamus and limbic system. These regulatory functions are potential therapeutic targets for vomeropherins..

Figure 1. Image of the nasal pasages in a human subject showing an area of nasal sensory receptors.

 

 

Figure 2. Brain activation induced by a vomeropherin in a human subject, revealed with functional magnetic resonance imaging (fMRI). The orientation of brain images is shown top to right. Images 1 and 2 had no activation and are not shown. Images 3-8 in the three conditions (sham, low concentration, high concentration) are shown from top to bottom, respectively. A robust increase in activation from the low concentration to the high concentration conditions is evident. Regarding regions of interest, activation is evident in the cingulated gyrus (images 3-8), in the inferior frontal gyrus (images 4-8), in the hypothalamus (image 5), in the limbic amygdala (image 6), in the thalamus (images 7-8).

 

Vomeropherins

The term "vomeropherin" refers to odorless substances that have a physiological or pharmacological effect as a consequence of binding to specific receptors in the human nasal passages and in the vomeronasal organ (VNO).

The various functions of the hypothalamus define the possible indications for treatment with vomeropherins. Pherin’s intellectual property portfolio includes composition of matter (novel compounds) and methods of use patents covering over 1,000 vomeropherins, genes encoding vomeropherin receptors and pharmaceutical applications of vomeropherins.

Vomeropherins act locally by binding to receptors in the mucosal lining of the nasal septum. By virtue of this local action, vomeropherins have a very rapid onset of action, as they do not require systemic absorption and distribution or crossing the blood-brain barrier to initiate their pharmacological effect. This is likely to provide vomeropherins with a significant therapeutic advantage compared to current therapies that require access to the systemic circulation followed by uptake into the brain in order to exert any effects.

The local action of vomeropherins in nasal chemosensory receptors leads to site-specific communication via a triggering of physiological responses in the hypothalamic-limbic regions of the brain. This targeted delivery and localized effect is in contrast to the broadcast-type communication, and more global effects within the brain and throughout the body that results when drugs are administered systemically.

The very low dosages at which vomeropherins are likely to be effective, together with their ability to be administered locally and the resultant limited anticipated exposure of the systemic circulation to these compounds provide an additional important potential therapeutic advantage for vomeropherins. There is minimal, if any, side effects or toxicity in laboratory animals. In addition, results of clinical trials indicate that vomeropherins are well tolerated and have a broad safety profile in humans. Finally, vomeropherins are administered by a non-invasive nasal spray or a nasal aerosol device, which is a convenient and well-established route of administration with a clear advantage for the patient.

Pherin’s research efforts are focused on those aspects of the chemistry, molecular biology and pharmacology of human vomeropherins that hold promise for development into efficacious and safe therapeutic applications. The Company’s scientific advisors and consultants provide ongoing advice as well as carry out projects in support of company objectives in their areas of expertise.

Selected References

Balas G. The putative pheromone androstadienone activates cortical fields in the human brain related to social cognition. Neurochemistry International 44: 595-600, 2004.

Berliner DL, Monti-Bloch L, Jennings-White C, Diaz-Sanchez V. The functionality of the human vomeronasal organ (VNO): evidence for steroid receptors. J. Steroid Biochem. Molec. Biol. 58(3): 259-265.1996.

Dulac C. and Axel R. A novel family of genes encoding putative pheromone receptors in mammals. Cell 83: 195-206, 1995. 

Grosser, B.I., Monti-Bloch L., Jennings-White C. and Berliner D.L.  Behavioral and electrophysiological effects of androstadienone, a human pheromone. Psychoneuroendocrinology. 25: 289-299, 2000.

Herman R. Human VNO cDNA libraries. Pherin US Patent. 2003.

Jacob, S., Garcia S., Hayreh D. and McClintock M.K. Psychological effects of musky compounds: comparison of androstadienone with androstenol and muscone. Hormones and Behavior 42: 274-283, 2002.

Lundstrom J.N., Olsson M.J., Schaal B. and Hummel T. A putative social chemosignal elicits faster cortical responses than perceptually similar odorants. Neuroimage 30(4):1340-6, 2006.

Monti D., Schapper A. and Monti-Bloch L. cAMP inhibits androstadienone induced Ca²⁺ currents in human vomeronasal organ (VNO) cells. Society for Neuroscience Abstracts, 1998.

Monti-Bloch L. and Berliner D.L. Comparison of the effect of human pheromones in the vomeronasal system of heterosexual and homosexual men. XV International Congress of the J. Steroid Biochem. Molec. Biol. Munich, Germany. 2002.

Monti-Bloch L, Jennings-White C. and Berliner D.L. The human vomeronasal system: a review. Annals of the New York Academy of Sciences, 885: 373-389, 1998.

Monti-Bloch L. Patch-recorded adult human vomeronasal organ cells are electrically excitable and respond to skin steroidal substances androsta-4,16-dien-3-one and estra-1,3,5(10),16-tetraen-3ol. Chemical Senses, 20(6): 745, 1995.

Monti-Bloch L., and Grosser B.I. Effect of putative human pheromones on the electrical activity of the human vomeronasal organ and olfactory epithelium. J. Steroid Biochem. Molec. Biol., 39(4B): 573-582, 1991.

Monti-Bloch, L., Jennings-White C., Dolberg D.S. and Berliner D.L. The human vomeronasal system. Psychoneuroendocrinology, 19: 673-686, 1994.

Rodriguez I., Greer C.A., Mok M.Y. and Mombaerts P. A putative pheromone receptor gene expressed in human olfactory mucosa. Nat. Genet. 26: 18-19, 2000.

Savic I., Berglund H., Gulyas B. and Roland P. Smelling odorous sex hormone-like compounds cause sex-differentiated hypothalamic activation in humans. Neuron, 31:661-668, 2001.

Savic I, Berglund H., and Lindstrom P. Brain response to putative pheromones in homosexual men. Proc Natl. Acad. Sci. U S A. May 17;102(20):7356-61, 2005.

Sobel N., Prabhakaran V., Hartley C.A., Desmond J.E., Glover G.H., Sullivan E.V. and Gabrieli J.D. Blind Smell: brain activation by an undetected airborne chemical. Brain, 122:209-217, 1999.

Winegar B. and Monti-Bloch L. Estrane pheromone-like substances increase cytosolic Ca²⁺ in isolated living human vomeronasal organ cells. Chemical Senses, ACHEMS Abstracts.