Inhibitors of the bitter taste response

Details Inhibitors of the bitter taste response Inhibitors of the bitter taste response

1999-12-22

2003-04-01

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Testing efficacy or toxicity of a compound or composition

C424S001110, C424S009100

Reexamination Certificate

active

06540978

ABSTRACT:

1. INTRODUCTION
The present invention relates to methods for identifying inhibitors of the bitter taste response, and by methods of using such inhibitors to either block the perception of bitterness and/or promote the perception of a sweet taste. The inhibitors of the invention may be used as flavor enhancers in foods and pharmaceuticals. The methods of the invention may further be used to characterize the gustatory perception of novel tastants.
2. BACKGROUND OF THE INVENTION
The sensation of taste has profound biological significance. It has much wider ramifications than merely providing mankind with pleasurable culinary experiences. Taste conveys numerous biological cues to humans and other animals, identifying tainted or spoiled foods and providing hedonic responses which may be proportionate to caloric or nutritive value.
There are generally considered to be only four or five categories of basic taste: sweet, sour, bitter, acid, and “umami” (the Japanese word describing the taste of monosodium glutamate; Hemess, M. S. & Gilbertson, T. A., 1999,
Annu. Rev. Physiol.
61:873-900). These can be sub-classified as the appetitive tastes, such as salty, sweet and umami, which are associated with nutrient-containing foods, and the bitter and sour tastes elicited by toxic compounds. The latter two produce an aversive reaction which may protect an organism by discouraging the ingestion of unhealthy or dangerous foods. Among the undesirable compounds associated with a bitter taste are plant alkaloids such as caffeine, strychnine and quinine, cyanide, and metabolic waste products such as urea (Lindemann, B., 1996,
Physiol. Rev.
76:719-766). It has recently been suggested that fat, the most energy-dense nutrient, may possess gustatory cues (Id., citing Gilbertson T. A. et al., 1997,
Am. J. Physiol.
272:C1203-1210 and Gilbertson, T. A., 1998,
Curr. Opin. Neurobiol.
8:447-452).
The anatomic basis for the initial events of taste is the taste receptor cell (“TRC”), located in clusters referred to as “taste buds” (Lindemann, supra). Taste buds are distributed throughout the oral cavity, including the tongue as well as extra-lingual locations (see Hemess and Gilbertson). In the human tongue, taste buds are organized into three specialized types of specialized structures, namely fungiform, foliate, and circumvallate papillae. Each taste bud comprises between about 50 and 100 individual cells grouped into a cluster that is between 20 and 40 microns in diameter. Nerve fibers enter from the base of the taste bud and synapse onto some of the taste receptor cells. Typically, a single TRC contacts several sensory nerve fibers, and each sensory fiber innervates several TRCs in the same taste bud (Lindemann, supra).
When a subject ingests a tastant, and that tastant encounters a taste receptor cell in the appropriate concentration, an action potential is produced which, via synapses with primary sensory neurons, communicates the signal registered by the receptor, via afferent nerves, to the appropriate region of the sensory cortex of the brain, resulting in the perception of a particular taste by the subject. Food appraisal can give rise to a hedonic response involving the activation of midbrain dopamine neurons (Lindemann, supra, citing Mirenowicz, J. & Schultz, W., 1996,
Nature
(
London
) 379:449-451) and the release of endogenous opiates (Lindemann, supra, citing Drenowski, A., et al., 1992,
Physiol. Behav.
51:371-379; Dum, J. et al., 1983,
Pharmacol. Biochem. Behav.
18:443-447).
Much research has been directed toward elucidating the physiology of taste. TRCs of most, if not all, vertebrate species possess voltage-gated sodium, potassium, and calcium ion channels with properties similar to those of neurons (Kinnamon, S. C. & Margolskee, R. F., 1996,
Curr. Opin. Neurobiol.
6:506-513). Different types of primary tastes appear to utilize different types of transduction mechanisms, and certain types of tastes may employ multiple mechanisms which may reflect varying nutritional requirements amongst species (Kinnamon & Margolskee, supra). For example, in the hamster, acid taste is associated with the influx of protons through an amiloride-sensitive sodium ion channel (Id., citing Gilbertson, T. A. et al., 1993,
Neuron
10:931-942), whereas in the mudpuppy, a proton block of potassium ion channels at the apical cell membrane is involved (Kinnamon & Margolskee, supra, citing Kinnamon, S. C. et al., 1988,
Proc. Natl. Acad. Sci. U.S.A.
85:7023-7027). Salty taste is typically transduced via permeation of sodium ions through amiloride-sensitive sodium channels.
Sweet taste has been associated with a second messenger system which may differ depending upon whether the tastant is a natural or artificial sweetener, the former believed to utilize cAMP, the latter inositol trisphosphate (IP
3
; Hemess M. S. & Gilbertson, T. A., 1999,
Annu. Rev. Physiol.
61:873-900). There is evidence that a membrane-bound receptor, such as that involved in the activation of G
s
and adenylyl cyclase, may be involved in the perception of sweet tastes (Id.).
Bitter taste sensations are also thought to involve cAMP and IP
3
(Kinnamon & Margolskee, supra). The bitter compound denatonium causes calcium ion release from rat TRCs and the rapid elevation of IP
3
levels in rodent taste tissue (Id., citing Bernhardt, S J. et al., 1996,
J. Physiol.
(
London
) 490:325-336 and Akabas, M. H., et al., 1988,
Science
242:1047-1050). Since denatonium cannot pass the cell membrane, it has been suggested that it may activate G-protein-coupled receptors, whereby the &agr; and/or &bgr;&ggr; G protein subunits would activate phospholipase C, leading to IP
3
generation and the release of calcium ions (Kinnamon & Margolskee, supra).
In recent years, a taste-specific G protein termed “gustducin”, which is homologous to the retinal G protein, transducin, has been cloned and characterized (Id., citing McLaughlin, S. et al., 1992,
Nature
(
London
) 357:563-569). Mice in which the a gustducin gene has been knocked out exhibit diminished responses to certain bitter (and certain sweet) tastants, suggesting that gustducin may regulate the TRC IP
3
response (Kinnamon & Margolskee, citing Wong, G. T. et al., 1996,
Nature
(
London
) 381:796-800). Introducing a wild-type rat &agr;-gustducin-encoding cDNA into &agr;-gustducin null mice restored their responsiveness to bitter and sweet compounds (Ming, D. et al., 1998,
Proc. Natl. Acad. Sci. U.S.A.
95:8933-8938, citing Wong, G. T., et al., 1996,
Cold Spring Harbor Symp. Quant. Biol.
61:173-184). Gustducin's &ggr; subunit (&ggr;
13
) has recently been shown to mediate activation of phospholipase C in response to the bitter compound denatonium (Huang, L. et al., 1999,
Nature Neurosci.
2:1055-1062).
Although it had been believed that rod and cone transducins were specific G proteins present only in photoreceptor cells of the vertebrate retina (Lochrie, M. A. et al., 1985,
Science
228:96-99; Medynski, D. C. et al., 1985,
Proc. Natl. Acad. Sci. U.S.A.
82:4311-4315; Tanabe, T. et al., 1985,
Nature
(
London
) 315:242-245; Yatsunami K. & Khorana, H. G., 1985,
Proc. Natl. Acad. Sci. U.S.A.
82:4316-4320), it was discovered that od transducin is also present in vertebrate taste cells, where it specifically activates a phosphodiesterase isolated from taste tissue (Ruiz-Avila, L. et al., 1995,
Nature
(
London
) 376:80-85). Using a trypsin-sensitivity assay, it was demonstrated that the bitter compound denatonium, in the presence of taste cell membranes, activates transducin but not the G-protein, G
i
(Id.). This activation could be inhibited by a peptide derived from the C-terminal region of transducin, which competitively inhibits the rhodopsin-transducin interaction (Id. and Hamm, H. E., et al., 1988,
Science
241:832-8359). Ruiz-Avila et al. (supra) proposed that transducin may be involved in bitter taste transduction via a cascade similar to that which occurs in visual perception, whereby a stimulated bitter receptor may activate taste-cell transducin, which in turn activate

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