Introduction

Drug discovery is extremely difficult. There are many unanticipated scientific, medical and business challenges to every drug discovery programme. It is important to increase our understanding of the fundamental properties of effective drugs so that we can anticipate potential problems in developing new agents. This article addresses potential drug discovery and development risks associated with the biochemical mechanism of drug action, and proposes simple rules to minimize these risks.

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Biochemical pharmacology

Biochemical pharmacology is concerned with the effects of drugs on biochemical pathways underlying the pharmacokinetic and pharmacodynamic processes and the subsequent therapeutic and the toxicological processes. The pharmaceutical process is, however, outside the realms of biochemical pharmacology.

The specific effects of neuroleptics in animals are well established. They interfere with the neuronal activity of the biogenic amines, dopamine (DA), noradrenaline (NA), and sometimes serotonin (5-HT). They may also influence the activity of other transmitters or mediators such as γ-aminobutyric acid (GABA), acetylcholine, and hormones, particularly prolactin. From these effects, the mechanism of antipsychotic action is concluded to be due mainly to DA-, rather than NA-receptor blockade in brain.

The condition sine qua non for the normal activity of the central nervous system is the continuous production of a sufficient amount of energy. Every function of the nerve cells or of the conducting elements requires either direct or indirect energy. The biochemical processes by which the brain cells derive this energy are very similar to those observed in other organs and in lower forms of life, though slight differences are not uncommon.

Thus, for example, unlike most other cell types, the brain cells in vivo appear incapable of using any other substance than glucose as their basic energy source. The carbohydrates play such a dominating part in the energy-producing processes of the nerve cells that it appears appropriate to begin this discussion with the metabolism of glucose.

Biochemical Effects of Fluperlapine

Fluperlapine was compared with clozapine, chlorpromazine, haloperidol and imipramine regarding its effects on some cholinergic and noradrenergic animal systems. Fluperlapine and clozapine showed the most pronounced anticholinergic effects. Fluperlapine was equipotent with clozapine in displacing [3H]-QNB from muscarinic receptors of the calf cerebral cortex (IC50 about 15 nM). In the mydriasis test in the mouse and in the crayfish hindgut bioassay the differences between fluperlapine and clozapine were small.

Like the other antischizophrenic drugs tested, fluperlapine displayed a marked affinity for α1-adrenoceptors (calf cerebral cortex: IC50 about 10 nM) but a neglible affinity for α2-adrenoceptors in the same tissue. Only clozapine showed a weak affinity for the latter receptor type.

Fluperlapine was as effective as imipramine in antagonizing tetrabenazine-induced ptosis in the rat, the antiptotic effect remaining constant after up to ten daily drug administrations. Still, imipramine was stronger than fluperlapine as an inhibitor of the accumulation of [3H]-noradrenaline ([3H]-NA) in rat cerebral cortex slices. Fluperlapine's effects on the spontaneous and the electrically-induced release of [3H]-NA from rat cerebral cortex slices, with and without protriptyline, showed it to be an inhibitor of the reuptake of NA.

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Clinical Pharmacology and Toxicology Research

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