Drug targets and mechanisms of action
المؤلف:
Stuart H. Ralston , Ian D Penman, Mark W J Strachan , Richard Hobson
المصدر:
Davidsons Principles and Practice of Medicine
الجزء والصفحة:
24th E , p14
2025-01-08
846
Modern drugs are usually discovered by screening compounds for activity either to stimulate or to block the function of a specific molecular target, which is predicted to have a beneficial effect in a particular disease (Box 2.2). Other drugs have useful but less selective chemical properties, such as chelators (e.g. for treatment of iron or copper overload), osmotic agents (used as diuretics in cerebral oedema) or general anaesthetics (that alter the biophysical properties of lipid membranes). The following characteristics of the interaction of drugs with receptors illustrate some of the important determinants of the effects of drugs:
- Affinity describes the propensity for a drug to bind to a receptor and is related to the ‘molecular fit’ and the strength of the chemical bond. Some drug–receptor interactions are irreversible, either because the affinity is so strong or because the drug modifies the structure of its molecular target.
- Selectivity describes the propensity for a drug to bind to one target rather than another. Selectivity is a relative term, not to be confused with absolute specificity. It is common for drugs targeted at a particular subtype of receptor to exhibit some effect at other subtypes. For example, β-adrenoceptors can be subtyped on the basis of their responsiveness to the endogenous agonist noradrenaline (norepinephrine): the concentration of noradrenaline required to cause bronchodilatation (via β2-adrenoceptors) is 10 times higher than that required to cause tachycardia (via β1-adrenoceptors). ‘Cardioselective’ β-adrenoceptor antagonists (β-blockers) have anti-anginal effects on the heart (β1 ), but may still cause broncho spasm in the lung (β2 ) and are contraindicated for asthmatic patients.
- Agonists bind to a receptor to produce a conformational change that is coupled to a biological response. As agonist concentration increases, so does the proportion of receptors occupied, and hence the biological effect. Partial agonists activate the receptor, but cannot produce a maximal signalling effect equivalent to that of a full agonist even when all available receptors are occupied.
-Antagonists bind to a receptor, but do not produce the conformational change that initiates an intracellular signal. A competitive antagonist competes with endogenous agonist ligands to occupy receptor-binding sites, with the resulting antagonism depending on the relative affinities and concentrations of the antagonist drug and endogenous agonist. Non-competitive antagonists inhibit the effect of an agonist by mechanisms other than direct competition for receptor binding with the agonist (e.g. by affecting post-receptor signalling).
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