PRECLINICAL IDENTIFICATION OF BETTER ANTIMUSCARINIC ANTIDEPRESSANTS

The recent reports that scopolamine has antidepressant effects in humans has raised the hope that this antimuscarinic drug represents an improvement over the serotonergic and noradrenergic reuptake blockers that have formed the basis for antidepressant medication for decades. Scopolamine's effects had a rapid onset of action, and were quite long lasting, giving them considerable advantage over previous medications. Of concern for the use of scopolamine in the treatment of depression is that scopolamine is used extensively in both human and animal studies to model cognitive deficits and dementia. There is, therefore, the likelihood that the antidepressant effects of scopolamine will coexist with the drug's well-known detrimental effects on attention, learning, and memory. The hypothesis on which the current proposal is based is that these two effects can be separated. They may, for example, be mediated by distinct receptor subtypes or by different efficacies at those receptors. Our plan is to evaluate selected antimuscarinic drugs in a series ofcoordinated assays designed to understand their profiles of activity. The assays will begin with in vivo evaluations to ascertain if a drug is a muscarinic antagonist centrally and peripherally. I so, its effects in antidepressant, and learning and memory assays will be described, and if a significantly smaller dose is necessary to produce antidepressant-like effects than to disrupt cognitive performance, its affinity and efficacy at the five muscarinic receptor subtypes will be measured. This will determine whether it is selectivity at one or more receptor subtype that confers antidepressant effects with reduced anti-cognitive effects. Chemical modeling will be applied to candidate compounds in attempts to improve their spectrum of activity so that there is an even greater pharmacological distinction between the desired and the off-target effects. Data obtained with our lead compound, L687,306 encourage our attempts to pursue this goal. According to the literature, L 687,306 is an M2 and M3 antagonist, has very slight efficacy at the M1 receptor, and is able to ameliorate the effects of scopolamine in cognitive tests. In our assays, it blocks the cardiovascular effects of arecoline, has discriminative stimulus effects in common with scopolamine, and is as active as scopolamine in the antidepressant assay. It is distinct from scopolamine in that it does not suppress ongoing behavior even at large doses, and it is able to competitively antagonize the suppressant effects of arecoline, which scopolamine cannot do. We anticipate that L 687,306 will have little effect on memory and attention until large doses are administered, since this drug has very little sedative effect and antagonizes scopolamine's anticognitive effects in similar assays. In vitro assays will indicate how the binding profile of L 687,306 differs from that of scopolamine, and on this basis, chemical modeling will be applied to improve on the presumed critical distinction. Through this process, we anticipate being able to specify the receptor mechanisms by which muscarinic antagonists ameliorate depression, how these are distinct from those that lead to impaired cognition, and to designate chemical entities that are likely to have an improved profile of antidepressant activity.