ABSTRACT
The phrase “physiological relevance” can have different meanings when used in a drug discovery context. A survey of the literature turned up three possible interpretations. The rst is when a target is relevant to the disease; the cells harboring the target have been referred to as physiologically relevant. For example, Panetta and Greenwood (2008) have written about the physiological relevance of G-proteincoupled receptor (GPCR) dimers as new drug targets for schizophrenia and preeclampsia (development of hypertension with proteinuria or edema, or both, due to pregnancy or the in uence of a recent pregnancy). Another example is voltage-gated calcium channels (VGCCs) as “physiologically relevant” targets for anxiety, epilepsy, hypertension, insomnia, and pain (Mohan and Gandhi, 2008). The second usage of the phrase is when the cell background is more relevant to the disease as the case may be for HTS methods that use primary and embryonic stem cells (Eglen et al., 2008). This is in contrast to the common practice in drug discovery where the immortalized cell employed in HTS is determined by the assay technology available; the recombinant targets are expressed in the immortalized cells followed by monitoring the drug interaction with the target using a simple quanti able response. To illustrate further, CHO cells expressing VGCC targets are more common (John et al., 2007) than “physiologically relevant” differentiated neural progenitor cells or embryonic stem cell-derived cardiomyocytes that naturally express VGCCs (Wagner et al., 2008; Yanagi et al., 2007). The third usage of the phrase is when 3D cells are involved with the accompanying difference in structure and function. To minimize the confusion, we introduce the phrase, “complex physiological relevance,” abbreviated as CPR. Hereafter, CPR is used to refer to 3D cells, in vitro, emulating in vivo structure and function that are absent in their 2D counterparts.
