Effect on ampa and kainate receptor antagonist activity of changing the terminal acidic group of n3-substituted willardiine derivatives J.C.A. More, N.P. Dolman, H.M. Troop & D.E. Jane. MRC Centre for Synaptic Plasticity, Dept. of Pharmacology, University of Bristol, Bristol BS8 1TD.

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Several N³-substituted willardiine derivatives with antagonist activity at AMPA and kainate receptors have been described in recent years (More et al., 2002; More et al., 2003). In the current study, the effect of changing the terminal acidic group of willardiine derivatives that have a benzene ring as part of the inter-acidic linker of the N³-substituent was assessed. Thus, the activities of (RS)-3-(4-tetrazol-5-ylbenzyl)willardiine (UBP285), (S)-3-(4-sulfobenzyl)-willardiine (UBP297) and (RS)-3-(4-phosphonobenzyl)-willardiine (UBP298) were compared to the previously reported compound (S)-3-(4-carboxybenzyl)willardiine (UBP282) (More et al., 2002; More et al., 2001) for activity at AMPA and GluR5-containing kainate receptors.

To measure GluR5-containing kainate receptor activity recordings were made from lumbar dorsal roots from 2-5 day old Wistar rats of either sex (4-13 g) (Agrawal & Evans, 1986). Non-cumulative concentration-response curves (CRCs) were constructed to kainate (1 min applications) in the continuous presence of Con A (1mg ml^-1) and in the absence and presence of the antagonists (100 µM; 30 min pre-incubation). To assess AMPA receptor antagonism, the ability of the compounds to block the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in neonatal rat hemisected spinal cords was measured (More et al., 2002). CRCs were constructed for the antagonists (5 min applications), in the presence of 2 mM MgSO₄ / 50 µM (R)-AP5 (30 min pre-incubation) to block NMDA receptors. Results are expressed as mean ± s.e.m., n=3 (Table 1).

Table 1: Antagonist activity at kainate and AMPA receptors

Each of the new compounds, UBP285, UBP297 and UBP298 was ~ 5-10-fold less potent as an AMPA receptor antagonist than UBP282. However, both UBP297 and UBP298 appear to be slightly more potent than UBP282 for antagonism of kainate responses on the dorsal root. This preliminary data suggests that changing the terminal acidic group of these compounds from a carboxyl group to either a sulfono- or a phosphono- group enhances selectivity for GluR5-containing kainate receptors over AMPA receptors. UBP285 and UBP298 are both racemates, and it is therefore likely that there will be an increase in potency once the active S enantiomer has been synthesized and tested.

Of the willardiine derivatives described so far, UBP297 is the most potent antagonist of kainate responses on the dorsal root. It is hoped that further structural changes using this information may lead to the development of compounds with higher potency and selectivity as AMPA or kainate receptor antagonists.

This work was supported by the MRC and Tocris Cookson Ltd.

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More, J., Troop, H., Dolman, N. et al., (2003) Br. J. Pharmacol. (in press).