Antagonist, neutral

It can be seen from Equation 6.69 that for a neutral antagonist (p=l) the correction term reduces to unity. Therefore as expected, 10 pA2 = KB. The negative logarithmic metameter of Equation 6.67 yields the expression for the pA2 ... 

A neutral antagonist binds equally to both active and inactive states of a G-protein-coupled receptor, regardless of activation state, and therefore blocks the actions of agonists and inverse agonists alike. 

In conclusion, H3 ligands offer the attractive vista of multiple applications in various disorders, but the ultimate definition of their therapeutic utility will have to await clinical trial results. Future work will determine whether inverse agonists, neutral antagonists, or protean agonists will constitute the more useful pharmacological intervention. 

Several groups have published on structural analogues of (382), one of the earliest being the disclosure of CP 272871 (383) from Pfizer, which displays lower affinity for the CBi receptor than (382), in addition to reduced selectivity over the CB2 receptor subtype. Both (382) and (383) have been shown to act as inverse agonists rather than neutral antagonists in vitro [265]. A recently published patent application from Sanofi-Aventis claims a series of 4-cyanopyrazole analogues of (382), with 42 specific examples [266]. 

A true antagonist lacking intrinsic activity ( neutral antagonist ) displays equal affinity for both the active and inactive states of the receptor and does not alter basal activity of the cell. According to this model, a partial agonist shows lower selectivity for the active state and, to some extent, also binds to the receptor in its inactive state. 

Fig. 4. Fluorescence lifetime distributions of /f2AR labeled at Cys265627 with fluorescein maleimide (Ghanouni et al., 2001a). (A) Single lifetime distributions are observed for unliganded receptor and receptor bound to the neutral antagonist alprenolol (ALP). (B and G) Two lifetime distributions are observed for /J2AR bound to the full agonist isoproterenol (ISO) and the partial agonist salbutamol (SAL). The short lifetime distribution for ISO is different from that for SAL, consistent with a different active conformation.

Recent developments that have led to the identification of inverse agonists (all classical antihistamines) and neutral antagonists might mean that a totally new group of Hj receptor-blocking compounds will shortly become available. 

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