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Abstract
Treatment compliance is reduced when pharmaceutical compounds have a bitter taste and this is particularly marked for paediatric medications. Identification of bitter taste liability during drug discovery utilises the rat in vivo brief access taste aversion (BATA) test which apart from animal use is time consuming with limited throughput. We investigated the suitability of using a simple, non-animal model, the amoeba Dictyostelium discoideum to investigate taste-related responses and particularly identification of compounds with a bitter taste liability. The effect of taste-related compounds on Dictyostelium behaviour following acute exposure (15 minutes) was monitored. Dictyostelium did not respond to salty, sour, umami or sweet tasting compounds, however, cells rapidly responded to bitter tastants. Using time-lapse photography and computer-generated quantification to monitor changes in cell membrane movement, we developed an assay to assess the response of Dictyostelium to a wide range of structurally diverse known bitter compounds and blinded compounds. Dictyostelium showed varying responses to the bitter tastants, with IC50 values providing a rank order of potency. Comparison of Dictyostelium IC50 values to those observed in response to a similar range of compounds in the rat in vivo brief access taste aversion test showed a significant (p = 0.0172) positive correlation between the two models, and additionally a similar response to that provided by a human sensory panel assessment test. These experiments demonstrate that Dictyostelium may provide a suitable model for early prediction of bitterness for novel tastants and drugs. Interestingly, a response to bitter tastants appears conserved from single-celled amoebae to humans.
Highlights
The ability to detect bitter substances is considered to have evolved to enable the recognition of toxic substances, which often present with a strong bitter taste (Mennella et al, 2013)
We investigated a range of compounds with diverse chemical structures and bitterness tailored to test if the model system is able to predict the bitterness of those compounds assessed in the in vivo rat brief access taste aversion (BATA) test and a human sensory panel (Clapham et al, 2012; Rudnitskaya, et al, 2013)
3.1 Dictyostelium cell behavior responds to acute application of bitter tastants Initial analysis of the effect of compounds representing the five basic taste groups on Dictyostelium used cells in the aggregation phase of development, with cell images recorded before (Fig. 1A) or after treatment (Fig. 1B)
Summary
The ability to detect bitter substances is considered to have evolved to enable the recognition of toxic substances, which often present with a strong bitter taste (Mennella et al, 2013). There are clear survival advantages to the rejection of bitter tasting foods and the induction of learned aversion in the wild (Glendinning, 1994) When such effects are induced by therapeutic agents, many of which have a bitter taste, they can have a negative impact on compliance with treatment, leading to sub-optimal therapy. In some cases it may be necessary to identify a different salt version of the API or even to change the API for another candidate, with clear implications for progression to the market and delay of patient access to a new therapeutic It is possible, at this stage, that the studies could be unblinded because
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