A molecular basis for drug action

Abstract

HE effect induced by a drug is the resultant of the interaction between T the molecules of the drug and the molecules of which the biological object is composed. The higher the specificity required in the structure of the drug molecule, the more probable it becomes that the effect is based on an interaction of these molecules with certain specific molecules in the biological object. These specific molecules are called the receptors for the drug. They can be defined as those specific molecules, molecule complexes or parts of them in the biological object, with which the drug must interact in order to induce its effect. The term receptor goes back to Ehrlich (1913) who said: "Corpora non agunt nisi fixata". The notion of a specific receptive substance as a site of action for drugs such as nicotine and curare in the myoneural junction was introduced by Langley (1905). Since then the term receptor has become indispensable in reasonings on the basis of drug action. Often the model of key and lock is used for the drug-receptor interaction; reality is much more dynamic, however. Schueler (1960) defined the receptor as follows : "The drug-receptor is in general the pattern R of forces of diverse origin forming a part of some biological system and having roughly the same dimensions as a certain pattern M of forces presented by the drug molecule in such a way that between patterns M and R a relationship of complementarity for interaction exists." Drug-receptor interaction must be seen as a mutual moulding of drug and receptor. There is mutual adaptation as far as shape and charge distribution is concerned. This adaptation plays an important role in the activation of drug and receptor and therefore is essential to drug action.Drug-receptor interaction can have various consequences.(a) The drug-receptor interaction mainly leads to changes in the charge distribution and shape of the drug molecule, in such a way that it is activated and becomes chemically more reactive, which results in chemical changes in the drug molecule. The drug is metabolised. The receptor is the "active site" on an enzyme.(b) The drug-receptor interaction mainly leads to changes in the charge distribution on and in the shape of the receptor, so that as a result of this the receptor becomes activated and induces changes in the charge distribution and shape of the surrounding molecules, thus initiating the sequence of physico-chemical events leading to the effect.(c) The drug-receptor interaction may take place without essential changes in the drug molecule or the receptor. No effect is then induced.

Pharmacological investigation into the effects of histamine and histamine analogues on guinea‐pig and rat colon in vitro

“…The present results show that histamine produces dose-dependent contractions in guinea-pig isolated longitudinal colon strips. The concentration-response curve to histamine of guineapig colon resembles that of guinea-pig ileum (Ariens, 1964) although the latter is more sensitive to histamine than the distal colon. These results agree with those on chicken gut, where regional differences have been found in the sensitivity to histamine of the gastrointestinal tract (Chand & Eyre, 1976).…”

Clonidine and presynaptic adrenoceptor theory

“…This would seem to allow for a variety of apparently contradictory effects on efflux contingent on the relative concentrations ofagonist and antagonist. However, as pointed out by Ariens et al (1964), partial agonists exhibit predictable effects in the presence offull agonists and these expectations need to be applied to clonidine.…”

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

“…The three phases of drug action, described by Ariëns (1), relate dose to pharmacological effect and are very well-known. In sequence, the pharmaceutical phase corresponds to the release of drug (active substance) from the dosage form, and comprises all physical processes involved in the disintegration of the form in which a compound was administered as well as the dissolution of the active substance in organic fluids (pharmaceutical availability).…”

“…In this regard, molecules which do not have suitable physicochemical properties would not overcome any of those three phases, limiting their use in clinical practice (1)(2)(3)(4). The main goal of pharmaceutical industries, nowadays, is to discover new, safe, effective, and orally administered chemical entities.…”