The cardiovascular therapeutic applications of most GPCR ligands to date are based on two fundamental premises. First, the drugs target the extracellular domains and specifically the ligand binding sites of the receptors, either mimicking the actions of the natural agonist ligands or blocking their access to the binding sites. Second, the receptor proteins have been considered molecular entities invariable in the human population. Both assumptions have recently been challenged. The clarification of the signal transduction pathways linked to GPCRs now allows the targeting of intracellular effector molecules and mechanisms responsible for receptor regulation. Such interventions are still mostly experimental but may provide more effective and selective, and thus safer, targeting of GPCR-mediated signaling pathways.37 In addition, it is becoming more and more evident that the interindividual variations in the human population with regard to physiological responses, including responses to GPCR agonists and antagonists are associated with the occurrence of naturally existing genetic variations in GPCRs and their effector molecules.32
Genetic tests for more accurate and earlier diagnoses will help classify hetero-genous populations of patients with cardiovascular diseases into genetically distinct groups. Genotyping before prescription of certain drugs may enable clinicians to predict how a patient will respond to a given treatment. This will allow the selection of appropriate therapies with the best benefit to the patient and also prevent the prescription of potentially toxic drugs that are likely to yield dangerous side effects in a genetically susceptible individual.38 The new molecular knowledge is also expected to facilitate the development of new drugs so that drug interventions may become more individualized.39
In spite of the apparent abundance of potential cardiovascular GPCR drug targets, only p-adrenoceptor antagonists and AT1 angiotensin antagonists are currently in widespread use in clinical cardiovascular therapeutics. Other types of receptors for monoamine neurotransmitters and vasoactive peptides are targets for a few classical cardiovascular drugs, such as atropine, and for newer drug classes with very specific actions, such as sumatriptan and related agents for treatment of migraine. The human genome project and concomitant advances in molecular medicine have, however, recently uncovered new potential drug targets: receptor subtypes with possibilities for drug actions with improved benefit:harm ratios; regulatory mechanisms influencing receptor gene expression and receptor functions; and genetic receptor variants offering opportunities for patient selection, risk profiling, and individualized therapy. More than 100 orphan GPCRs still await characterization, and some of them may turn out to be valid cardiovascular drug targets. It is a major challenge for biomedical research to elucidate their physiological functions and therapeutic potentials.
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