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life Sciences, Vol. 65, No. 10, pp. %7-980,1999 Copyright 0 1999 Elaevier Science Inc. Printed in the USA. All rights reaavd 00243205/99/s-set front mattes ELSEVIER

PII SOO24-3205(99)00197-6

Robert B. Raffa
Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pharmacology, School of Medicine, TempleUniversity, Philadelphia, PA 19140, U.S.A. (Received in final form April 26.1999)

A core concept in pharmacology is drug-receptor affinity, i.e., the tendency of a drug molecule to bind to one or more receptors due to the collective influence of multiple molecular forces. The estimation of affinity as a dissociation constant (reciprocal of the equilibrium constant) is extraordinarily valuable.However, elucidation of the nature of the underlying concept--i.e., what acco~lt~ for affinity-is not achievable using such a static measure. Observing how the system responds to a perturbation (e.g., to a change in temperature) reveals more fundamental information. The present review summarizes the general concepts of thermodynamic analysis applied to drug-receptor interactions and discusses‘extrathermodynamic’ phenomena, such as enthalpy-entropy ‘compensation’. Together, these concepts may provide insight into the nature of drug-receptor interactions, begin to elucidate the forces that underlie such interactions-and begin to define and refine more nebulous terms such as @nify.
Key Words: thermodynamics, enthalpy, entropy, free energy, drug-receptor interaction

Drug-receptor affmity canbe described operationally as, for example “The chemical property that causes the drug to remain associated with the receptor.. .” (1) and many methods have been developed that measure affinity, or at least estimate it (see, e.g., texts l-4). The widely-used dissociation constant (reciprocal of the equilibrium constant) is a case in point. Such methods have been applied to studies in vitro and inviva,and their successful application to receptor classification has validated the utility of the approach. However, the temperature-dependence of the dissociation constant can reveal additional characteristics of the interaction that are beyond the resolution power of the dissociation constant (e.g., 5) and leads to the determination of quantities that are analogous to thermodynamic parameters(see reviews 6,7,8, Table 1). Although understandably suspect to the thermodynamics purist, the literature suggests that such an analysis leads to quantities for the change in free energy (AW), enthalpy (AH’) and entropy (AS”) that are consistent with what is known about the interaction.

Re.print requests: Robert B. Raffa, Ph.D., Temple University School of Pharmacy, 3307 N. Broad Street,Philadelphia, PA 19140.


Drug-Receptor Thermodynamics

Vol. 65, No. 10, 1999

TABLE 1 Background and Definitions The historical development and full mathematical treatment of thermodynamic quantities and concepts are available in several recent excellent texts (e.g., 9-l 1). The following are concise operational descriptions that incorporate the conditions and approximations generallyapplicable to chemical reactions in solution (e.g., constant volume): . . Chanpe (AU or AE): as in AU = q + w , it is the sum total of the energies (excluding kinetic and potential) that is exchanged by the system with the surroundings as the heat added (+ q ) or subtracted (- q ) and the work done on (+ w ) or by (- w ) the system. Chance (AH): sometimes referred to as the ‘heat content’, thisparameter is related to the internal energy by H=U+ pV and represents the quantity of energy that is added (edhermic reaction) or liberated (exothermic reaction) (AH > 0 and < 0, respectively) by a process for a system that is at constant pressure and mass. In pharmacolo ic studies. AH is commonly interpreted as reflective of changes in intermolecular forces between 5.lgand and receptor (primarily...
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