Cardiovascular diseases constitute a major focus area for drug discovery and development. They are very prevalent in all populations, and many therapeutic needs are still unmet despite the many successes of the past 50 years. It is evident from Table 4.1 that relatively few GPCRs are currently exploited as cardiovascular drug targets, even if p-adrenoceptor and AT1 receptor antagonists represent two of the most widely used drug classes in modern medicine.
Table 4.2 summarizes information on novel drugs targeted to GPCRs that are currently in various phases of clinical development (see www.centerwatch.com). In addition, many types of GPCRs are currently undergoing validation as potential cardiovascular drug targets and numerous drug candidates are in various stages of preclinical development. Even if promising preclinical lead compounds have been identified in many cases, proof of concept can be obtained only after efficacy and safety have been at least preliminarily evaluated in clinical trials. Table 4.2 also indicates that relatively few receptor types are targets for novel drugs that have already entered various phases of their clinical testing programs. Of the drugs and drug targets listed in Table 4.2, some represent novel therapeutic approaches.
Antagonism of cardiac serotonin 5-HT4 receptors represents a novel approach to treat atrial fibrillation by blocking 5-HT4 receptor-mediated enhancement of atrial
Examples of Novel Drugs in Clinical Development, Targeted to Cardiovascular GPCRs
Target Receptor and Action Drug
5-HT1a agonist Repinotan
5-HT1B/2A antagonist SL 65.0472
5-HT4 antagonist a2B/C adrenoceptor antagonist A1 antagonist A1 agonist A2A agonist
Tezosentan Conivaptan OPC-41061 SR 121463
Cerebral ischemia Stroke
Piboserod Atrial fibrillation
OPC-28326 Raynaud's disease
Peripheral vascular disease CVT-124 Congestive heart failure
Tecadenoson Arrhythmia Binodenoson Coronary artery disease, diagnosis
CVT-3146 Coronary artery disease, diagnosis
TBC-3711 Congestive heart failure
Hypertension Darusentan Congestive heart failure
Hypertension Ambrisentan Congestive heart failure Hypertension Congestive heart failure
Congestive heart failure Congestive heart failure Congestive heart failure
II II II
II II II
Sanofi-Synthelabo Pharmaceuticals GlaxoSmithKline Otsuka America Pharmaceutical Biogen Idec CV Therapeutics King Pharmaceuticals
Pharmaceutical Otsuka America Pharmaceutical Sanofi-Synthelabo Pharmaceuticals
Source: Data extracted from CenterWatch online directory of drugs in clinical trials (http://www. centerwatch.com).
contractility and relaxation. a2-Adrenoceptors are known to mediate constriction of blood vessels, and they have been identified as potential targets in the treatment of Raynaud's disease and other forms of peripheral vascular disease, e.g., intermittent claudication. The unwanted consequences of central a2A-adrenoceptor antagonism have so far invalidated this approach; targeting of peripheral a2B- and a2C-adreno-ceptors may overcome this problem.
Adenosine is currently in limited clinical use to terminate supraventricular arrhythmias and to dilate coronary arteries in diagnostic imaging procedures — two effects mediated by two different receptor subtypes (A1 and A2A). Both effects are now pursued separately with subtype-selective agonists. In addition, an antagonist of A1 adenosine receptors is in clinical development for therapy of congestive heart failure, based on its capacity to promote renal excretion of sodium and water.
Receptors for calcitonin gene-related peptide (CGRP) are abundant in vascular smooth muscle and endothelium, and activation of these receptors is known to cause relaxation of blood vessels. Olcegepant is an antagonist of at least some types of CGRP receptors and is in clinical development for migraine and cluster headaches. Bosentan is currently in limited clinical use as a vasodilator in pulmonary hypertension, but other small-molecule endothelin receptor antagonists are now under clinical development for broader therapeutic indications, including hypertension and congestive heart failure. Vasopressin V2 receptor antagonists are also in clinical development for congestive heart failure, based on their capacity to oppose vaso-pressin-induced vasoconstriction and renal fluid retention.
In addition to the identification of various GPCR subtypes involved in cardiovascular regulation recently expedited by the efforts and results of the Human Genome Project, exploitation of these receptors as cardiovascular drug targets requires their thorough physiological and pharmacological characterization. Their distributions in tissues and cell types must be mapped; their coupling and signaling mechanisms elucidated; the mechanisms involved in their functional regulation determined; and their roles in cardiovascular development and plasticity identified. Sufficiently selective pharmacological ligands have not in all cases been available to reliably differentiate the functions mediated by different but closely related GPCR subtypes. For instance, until recently, the study of the physiological roles and therapeutic potentials of the three different genetic a2-adrenoceptor subtypes was difficult.5 The recent employment of homologous recombination methodologies has produced mouse lines with selective deletions, mutations, or overexpression of individual GPCR subtypes, and has permitted the elucidation of the specific contributions of the different a2-adrenoceptor subtypes in cardiovascular regulation.67
It has been demonstrated for most GPCRs that receptor activation initiates a process responsible for receptor desensitization (i.e., waning of stimulated responses) and internalization (i.e., removal from the plasma membrane, thus making the receptors unavailable to extracellular ligands).8 The process of agonist-dependent desensitization includes uncoupling of the receptors from G proteins as a result of phosphorylation of residues in their intracellular domains (most commonly demonstrated for the third intracellular loop) by specific phosphorylating enzymes, the GPCR kinases (in particular GRK2 and GRK3).9
Receptor phosphorylation promotes the binding of p-arrestins that sterically hinder receptor coupling to G proteins and also interact with a variety of proteins involved in endocytosis, acting as scaffolds to transduce and compartmentalize alternative signals. GRK2 activity is regulated by complex protein phosphorylation cascades, including phosphorylation by mitogen-activated protein kinases. Understanding of the mechanisms regulating receptor responsiveness may suggest novel drug targets for cardiovascular therapy, perhaps allowing more physiological and more finely tuned approaches than direct GPCR activation or antagonism.
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