Receptor pharmacology

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

The discovery of constitutive receptor activity uncovered a major new idea in receptor pharmacology namely, the concept of negative efficacy and inverse agonism. 

Chen, W.-J., Armour, S., Way, J., Chen, G., Watson, C., Irving, P., Cobb, J., Kadwell, S., Beaumont, K., Rimele, T., and Kenakin, T. P. (1997). Expression cloning and receptor pharmacology of human calcitonin receptors from MCF-7 cells and their relationship to amylin receptors. Mol. Pharmacol. 52 1164-1175. 

A basic premise in receptor pharmacology is that all drugs have affinity for receptors (the chemical property that unites the dmg with the receptor), and some drugs have efficacy, the chemical property that causes the receptor to change its behavior toward its host cell. Drugs that have efficacy can produce concentration-dependent responses in physiological systems, characterized by a concentration-response curve (also often referred to as a dose-response cuive). 

A basic concept in receptor pharmacology is the idea of orthosteric and allosteric interaction. Orthosteric interaction occurs when two molecules compete for a single binding domain on the receptor. With allosteric interactions two molecules each have their own binding domain on the receptor and the two interact through effects on the protein (conformational change). Tims, with orthosteric interactions only one molecule may occupy the receptor at any one instant whereas with allosteric interactions both molecules can bind to the receptor at the same time. There are implications for... 

Pritchett DB, Seeburg PH Gamma-aminobutyric acidA receptor alpha3-subunit creates novel type II benzodiazepine receptor pharmacology. J Neurochem 34 1802-1804, 1990... 

Lynch DR, Guttmann RP (2001) NMDA receptor pharmacology perspectives from molecular biology Curr Drug Targets 2(3) 215-231... 

In between the above two extremes are the monoamines (1-lOnmol/g) which are preformed and stored in terminals but at much lower concentrations than the amino acids and when released are removed primarily by reuptake for re-use, or intraneuronal metabolism to inactive metabolites. Thus the appropriate synaptic organisation, biochemistry and receptor pharmacology of the NTs also varies in keeping with their function. It is often assumed, incorrectly, that the NTs found in the highest concentration are the most potent. In fact the opposite is true. Those like the amino acids while having high affinity for their receptors have low potency while the peptides found at much lower concentration have high potency but low affinity. 

Figure 3.3 Molecular structure of G-protein-coupled receptors. In (a) the electron density map of bovine rhodopsin is shown as obtained by cryoelectron microscopy of two-dimensional arrays of receptors embedded in lipid membrane. The electron densities show seven peaks reflecting the seven a-helices which are predicted to cross the cell membrane. In (b) is shown a helical-wheel diagram of the receptor orientated according to the electron density map shown in (a). The diagram is seen as the receptor would be viewed from outside the cell membrane. The agonist binding pocket is illustrated by the hatched region between TM3, TM5 and TM6. (From Schertler et al. 1993 and Baldwin 1993, reproduced from Schwartz 1996). Reprinted with permission from Textbook of Receptor Pharmacology. Eds Foreman, JC and Johansen, T. Copyright CRC Press, Boca Raton, Florida...

Jenkinson, DH (1996) Classical approaches to the study of drug-receptor interactions. In Textbook of Receptor Pharmacology (Eds Foreman, JC and Johansen, T), CRC Press, Boca Raton, FL, pp. 159-185. 

Figure 11.9 GAB Ac receptor pharmacology and structure, (a) Various GAB Ac agonists and antagonists described in the text. Picrotoxinin is the active component of picrotoxin and also acts at GABAa receptors, (b) Presumed subunit structures of GABAc receptors. The receptors can form as homomeric assemblies of p subunits but native receptors may be heteromeric assemblies of p subunits (e.g. pi and p2) or may contain both p and y subunits...

Figure 11.10 Glycine receptor pharmacology and structure, (a) Amino acids that act as agonists at glycine receptors, and strychnine a competitive antagonist, (b) Subunit composition of foetal and adult glycine receptors in the spinal cord. The receptors are shown with a pentameric assembly but the a. and subunits are distinct from those that form GABAa receptors. Picrotoxin is also an effective glycine antagonist and in recombinant systems is selective for homomeric receptors...

Bowery, NG (1993) GABAb receptor pharmacology. Ann. Rev. Pharmacol. Toxicol. 33 109-147. 

The most important class of CBi receptor antagonists identified to date are the 1,5-diaryl-pyrazoles. This class includes rimonabant (382), first described in patent applications from Sanofi just over a decade ago [263, 264]. Rimonabant has proved invaluable in the elucidation of carmabinoid receptor pharmacology, as described in the section on therapeutic applications below. 

The cannabinoid field was reviewed in Progress in Medicinal Chemistry Volume 35. Since that time great advances have been made in our understanding of cannabinoid receptor pharmacology. Many novel ligands have been discovered and several are expected to have exciting clinical utility. Medicinal chemistry approaches to the modulation of cannabinoid receptors are extensively reviewed in Chapter 6. 

Jacobson KA, van Galen PJM, Williams M. Adenosine receptors pharmacology, structure-activity relationships, and therapeutic potential. J Med Chem 1992 35 407 122. 

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