Pharmacology, reverse

Reverse pharmacology has great possibilities in drug discovery. Classical pharmacology starts with an active molecule and then looks for its effects and the receptor or enzyme through which these effects are exerted. For example, acetylcholine (ACh) was known from Loewy s experiments and from other studies in the periphery as an active substance. The target must be, by definition, an acetylcholine receptor. You knew it must exist you already had a name for it when you found it and all you had to do was find it, localize it, and discover its physicochemical, biochemical, and pharmacological characteristics. 

Academic scientists would of course go for a biological Proof of Principle. They would immediately delete the gene (i.e., make a knockout transgenic animal) and look for a phenotype. A Pharma company would, sooner or later, license this transgenic animal from the academic scientists to know if the compound they have made is specific. It should not work at all in the knockout animal if the drug is 100% specific since the target is not expressed and does not exist or occur in the knockout animal. The only interactions that should be present will be those responsible for causing side effects. This is very useful. 

A few recent, real examples will indicate some of the possibilities and potential of this approach. 

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A scientific procedure that turns the classical pharmacology approach upside down. Instead of finding the elusive receptor for a known hormone or transmitter what classical pharmacology aims at, reverse pharmacology is initiated through the discovery of the receptor gene and aspires to the identification of the receptors unknown ligand. 

Patwardhan B, Vaidya ADB. (2010) Natural product drug discovery Accelerating the clinical candidate development using reverse pharmacology approaches. Indian J Exp Biol 48 220-227. 

Kreienkamp HJ, Larusson HJ, Witte I, et al. Functional annotation of two orphan G-protein-coupled receptors, Drostarl and -2, from Drosophila mela-nogaster and their ligands by reverse pharmacology. J Biol Chem 2002 277 39937-39943. 

Brinkmann, V. (2007). Sphingosine 1-phosphate receptors in health and disease Mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther. 115(1), 84-105. 

The concept of a direct and rapidly reversible pharmacological response implies that the intensity of response is directly associated with the drug concentration at the site of action. In this category, two models (pharmacodynamic and pharmacokinetic-pharmacodynamic) are discussed. 

Most drugs produce a reversible pharmacological response. However, some antibiotics, irreversible enzyme inhibitors, and anticancer agents incorporate irreversibly or covalently into a cell s metabolic pathway. This results in an irreversible effect—cell death. Complex kinetic models are used to explain the relationship of dose-chemotherapeutic effects for some drugs, such as methotrexate, cyclophosphamide, and arabinosylcytosine.f ... 

Clindamycin and hncomycin potentiate the action of nondepolarizing neuromuscular blocking drugs, such as pancuronium and D-tubocurarine. The lincosamide-induced block cannot be reliably reversed pharmacologically (71). 

Michimata M, Fujita S, ArakiT, Mizukami K, Kazama I, Muramatsu Y, Suzuki M, kImuraT, Sasaki Ss, Imal Y, Matsubara M. Reverse pharmacological effect of loop diuretics and altered rBSCl expression In rats with lithium nephropathy. Kidney Int 2003 63(1 ) 165-171. 

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