Bevan, Kathryn Anne; (1995) Dextromethorphan binding sites in mammalian brain and their significance in neuroprotection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The non-opioid antitussive agent dextromethorphan (DM) has recently been found to possess neuroprotective and anticonvulsant properties, though the precise mechanism of action is unknown. High affinity binding sites have been identified in brain, which may mediate the neuroprotective properties of DM and related compounds. However, DM is also active at the N-methyl-D-aspartate (NMDA) receptor-associated ion channel blocking site (the "PCP site"), which is known to be involved in mediating calcium influx during ischaemia-induced neurodegeneration. In addition, DM is rapidly metabolised in vivo to dextrorphan, which also binds to the PCP site with higher affinity than the parent compound. Radiolabelled DM ([3H]DM) binding was compared in normal and ischaemic rat brains. In normal brains DM binding sites were ubiquitously distributed, with highest levels of binding found in the midbrain, hindbrain and cerebellum (50-70 fmol/mg). In brains which had been subjected to an ischaemic insult, some differences from normal were suggested in certain brain regions. Decreases in [3H]DM binding were apparent in the occipital, parietal and temporal cortices (-40-50%), and in the midbrain, hindbrain and cerebellum (-30-40%), while in the hypothalamus, thalamus and amygdala, increases in binding were observed (+40-85%). To determine the relative contribution of binding to DM sites and PCP sites to the neuroprotective effect of DM, the binding activity of a series of chemical analogues of DM and carbetapentane, another antitussive agent which also binds to DM sites, were evaluated at both DM sites and PCP sites (labelled with [3H]TCP) in rat brain. DM was found to possess approximately 4-fold greater selectivity for DM sites when compared with PCP sites (IC50S of 450nM and 2μM, respectively). However, several compounds were identified which retained significant affinity for DM sites (100nM- 5μM), but which were inactive at PCP sites (>>10μM). In addition, shallow displacement curves were observed, indicating the presence of more than one site for [3H]DM binding. Consistent with previous reports, DM was neuroprotective in a middle cerebral artery occlusion model of focal ischaemia in rats (ED50 approximately 70mg/kg, sc.). Carbetapentane was approximately four-fold more potent as a neuroprotective agent than DM in this model. Of particular interest was the marked neuroprotective potency of the methyleneoxy derivative of carbetapentane, compound 11, which was eighteenfold more potent than DM. This was significant as this compound showed no activity at PCP sites. Furthermore, being structurally distinct from DM, the neuroprotective activity of compound 11 could not be explained by metabolism to dextrorphan in vivo. Thus programmes selectively targeting DM binding sites could represent opportunities for the development of a new class of neuroprotective agents.

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