John H. Biel

CHOLINERGIC BLOCKADE AS AN APPROACH TO THE DEVELOPMENT OF NEW PSYCHOTROPIC AGENTS

The emergence of the psychotropic drugs as effective therapeutic agents in the treatment of mental disorders and the subsequent attempts to elucidate their mechanism of action, brought to the forefront a number of endogenous substances that had previously been thought to be concerned only in the control and transmission of autonomic nerve impulses (FIGURE 1). The effects of the psychotropic agents were described in terms of mimicking, potentiating, or inhibiting the actions of these endogenous substances, and this led to the conclusion that the subcortical centers of the brain might be subject to similar autonomic controls as the remainder of the body physiology. Thus Brodie’ expanded the hypothesis of Hessz (FIGURE 2), which postulated an ergotropic (excitatory) center and a trophotropic (depressant) center in the hypothalamus. Norepinephrine was thought to be the neurohormone involved in ergotropic stimulation while serotonin or acetylcholine were concerned in trophotropic stimulation. Substances that mimicked or potentiated the actions of norepinephrine such as the sympathomimetic amines and its “masked” analogues (pipradol, methylphenidate) or prevented its metabolic destruction (MA0 inhibitors) produced mood elevation, antifatigue effects, and an antidepressant action in depressed mental patients. Conversely, an inhibition of the ergotropic stimulator, norepinephrine, by the administration of blocking agents such as the chlorpromazine-type drugs or ethoxyb~tamoxan~ resulted in a calming and tranquilizing action. This theory was further substantiated by the development of substances that prevented the synthesis of norepinephrine from its carboxylic acid precursor dihydroxyphenylalanine (DOPA) , the socalled DOPA decarboxylase inhibitors (FIGURE 3 ) . These compounds likewise exerted a sedative and depressant effect on the CNS.4 By the same token, blockade of trophotrophic stimulators should lead to central stimulation and excitation. While serotonin antagonists have exhibited no such properties, a number of drugs with potent anticholinergic properties have demonstrated antidepressant effects (FIGURE 4). For instance, Benadryl is a fairly potent sedative, while its o-methyl congener, Disipal, is not a t all sedative and may even cause e ~ p h o r i a . ~ Its anticholinergic action is twice that of Benadryl. Benactyzine is a potent anticholinergic that has been applied successfully in the treatment of depression when used in conjunction with meprobamate.6 Tofranil, one of the newer antidepressant drugs, is a moderately potent anti~holinergic~ and Pacatal whose action is less sedative than that of chlorpromazine is also a much more potent inhibitor of acetylcholine.8 The work of Finkg with several experimental anticholinergic compounds

STRUCTURE AND ACTIVITY RELATIONSHIPS OF MONOAMINE OXIDASE INHIBITORS

The advent of the tranquilizing drugs brought about a definite change in the philosophy of the treatment of mental disease. At least two benefits accrued from this change in our thinking: (1) it pointed a way toward the eventual physiological treatment of mental disease, and (2) it raised the possibility that certain therapeutic concepts and techniques that had dealt successfully with diseases other than mental could be extended and applied in the treatment of psychiatric disorders. The concepts to which I refer concern themselves primarily with the roles of such familiar chemical mediators of normal and abnormal physiological functions as acetylcholine, norepinephrine, epinephrine, histamine, and serotonin, as well as with the variety of approaches of potentiating and inhibiting their pharmacological effects. In other words, by chemically manipulating these endogenous substances we had been able to hand-control certain bodily processes that had begun to malfunction because of a breakdown in the once carefully balanced automatic control mechanism (homeostatic equilibrium) of the body. Diseases such as peptic ulcer, ulcerative colitis, biliary disorders, hypertension, allergic manifestations, and asthma could be treated in this fashion, a t least symptomatically. The work of Brodie,l Woolley,2 G a d d ~ m , ~ and Mills and Slater4 indicated that similar physiological mechanisms might be operating in the brain, and that their potentiation or inhibition might result in a practical approach to the treatment of mental disease. In the light of these concepts I shall review briefly the subject of central stimulants and then present in greater detail some of the newer approaches to the chemotherapy of the depressive state that are being attempted in our laboratories. The status of the central stimulants up to 1955 was perhaps adequately summed up by Goodman and Gilman5 in the second edition of The PharmacoZogical Basis o j Therapeufics : “Although central nervous system stimulants are sometimes dramatic in their pharmacological effects, they are relatively unimportant from a therapeutic point of view. It is not possible to stimulate the central nervous system for a long period of time, for heightened nervous activity is followed by depression, proportional in degree to the intensity and duration of the stimulation. Consequently, therapeutic excitation of the central nervous system is usually of brief duration and is reserved for emergencies characterized by severe central depres~ion.”~ This statement was based, of course, on the action of those drugs available a t the time for stimulation of the central nervous system (CNS). Such agents are picrotoxin, metrazol, strychnine, camphor, nikethamide, and caffeine. Picrotoxin and metrazol were used most often in respiratory depression resulting from barbiturate poisoning. Metrazol and camphor were, of course,