Computer analysis of a file of psychotropically active compounds. V. relationship between test results for experimental animals and model enzyme systems

Abstract

It was found that the number of tests required to split up the training sample correctly into forms of activity and to give a correct forecast on the activity for new compounds can be reduced considerably: Good results are obtained for certain forms containing only 12 features. The set of tests on which the assignment was made in the papers cited above was, however, in essence a random one. The use of new data that throw light on the mechanisms of action of drug groups [8] serve to explain and refine the previous results [I, 2] somewhat. It has been found [8] that almost all groups of psychotropic drugs inhibit transport Na,K and Ca,Mg ATPases to a greater or smaller extent. The action is unspecific and unselective. The drugs most activein this respect are neuroleptics, followed by hypnotics and spasmolytics. In our data, the action is dependent on the effects of the drugs on the structure of the lipid part of membranes; it is correlated fairly closely with the general depressive action, and comparative pharmacological studies indicate inhomogeneity in the sedative effect. The effects on the dopamine- and noradrenaline-sensitive adenyl cyclase are more selective. Neuroleptics have a blocking action on the dopamine-sensitive adenyl cyclase; tricyclic antidepressants interact with noradrenaline-sensitive adenyl cyclase. The interaction with the D2-dopamine receptor reflects more precisely the mode of action of the neuroleptics. Here we consider the choice of the test contained in the reduced forms of [i] on the basis of data on enzyme inhibition by these groups of psychotropic drugs (neuroleptics, antidepressants, psychostimulants, tranquilizers, and hypnotics). It is shown that the number of necessary features can be further reduced to seven. We have also obtained data that to some extent explain the physiological meaning of the animal response to the drugs. For these purposes we have examined the correlations between the test results for 84 psychotropic drugs used in vivo with the tests of [i] as against the results from the inhibiting action in vitro on the Na,K ATPases in the brain, and on the dopamine- and noradrenalinesensitive adenyl cyclase from the striatum and limbic region of the brain. The interaction of the drugs with the enzymes was examined by the method of [8]. We excluded from consideration the results of seven tests (Nos. i0, ii, 12, 15, 17, 19, 20, and 34 in the numbering of [i]), which reduced the cross-correlation to zero. We therefore examined only 30 experimental features, not 37.