Defining the Role of Pharmacology in the Emerging World of Translational Research

Abstract

Pharmacology is focused on studying the effects of endogenous agents and xenobiotics on tissue and organ function. Analysis of the concentration/response relationship is the foundation for these assessments as it provides quantifiable information on compound efficacy, potency, and, ultimately, side-effect liability and therapeutic index. Historically, pharmacology has been viewed as a unifying, hierarchically integrated, and technologically agnostic discipline. Besides being important in the development of new medications, pharmacological research has led to a better understanding of disease pathogenesis and progression. By defining the effects of compounds in vitro and in vivo, pharmacology has provided the means to validate, optimize, and advance new chemical entities (NCEs) to human testing. With the advent of molecular biology-based assay systems and a technology-driven (high-throughput screening, combinatorial chemistry, SNP mapping, systems biology) reductionistic focus, the integrated, hypothesis-driven pharmacological approach to drug discovery has been de-emphasized in recent years. This shift in research emphasis is now viewed by many as a major factor in the decline of new drug approvals and has led to various initiatives, the most notable being the Critical Path and Phase 0 clinical trial initiatives launched by the US Food and Drug Administration (FDA). These programs underscore the growing need for individuals trained in integrative pharmacology and having a background in molecular pharmacology to drive the drug discovery process and to fostering the translational research that is now considered vital for more rapidly identifying novel, more effective, and safer medications.

Introduction

Molecular pharmacology evolved in the mid-twentieth century as a result of advances in biochemistry. This approach to studying drug actions provided a potentially facile means for identifying sites that may be targeted for more precisely attacking the pathophysiology of disease processes. By adding to a systematic, heuristic framework for defining the mechanisms of disease causality, molecular pharmacology has become a critical component of the in vitro/in vivo hierarchy of assay systems used for evaluating hypotheses in the drug discovery process.

The importance of the contributions of molecular pharmacology to biomedical research is reflected in the number of Nobel Prizes in medicine awarded over the past 50 years for fundamental discoveries in disease causality and the manner in which drugs affect these processes. Thus, the prize has been given for discoveries relating to mechanisms for the storage, release, and inactivation of humoral transmitters; the action of hormones; signal transduction in the cardiovascular and nervous systems; peptide hormone production; regulation of cholesterol metabolism; and the establishment of modern mechanistic principles for drug treatment. With respect to the last topic, the Nobel Prize was awarded to Gertrude Elion, George Hichens, and Sir James Black for their discoveries relating to particular drug entities, namely azathioprine, acyclovir, and the H₂ receptor blocker cimetidine (http://nobelprize.org/nobel_prizes/medicine/laureates/index.html).

These successes solidified the molecular approach to drug discovery and this research orientation subsequently expanded to include gene cloning techniques, leading to an increased emphasis on transcriptional and translational processes as drug targets (Celis et al., 2000). However, the impact of the characterization of the human genome (International Human Genome Sequencing Consortium, 2004) has fallen far short of its predicted utility for, and impact on, drug discovery (Collins et al., 2003). While this is probably due, in part, to an oversimplification of the target validation process (Kopec, Bozyczko-Coyne, & Williams, 2005) and highly optimistic time lines, the human genome effort still has a far reaching influence in regard to the design of research programs aimed at defining drug mechanisms of action, efficacy, and side-effect profiles.

The late 1960s witnessed a resurgence of the receptor–ligand concept, at that time some 100 years old (Maehle, Prüll, & Halliwell, 2002). The delay in acceptance was due, in part, to the fact that it took time to convince a majority of biomedical scientists that drug receptors were cell surface entities through which medications exert their actions (Kenakin, 2009, Rang, 2006).

The notion that intracellular proteins might also function as drug targets was given little consideration, however. Thus, potential roles for small molecules interacting with DNA (Chenoweth & Dervan, 2009), ATP-binding proteins (e.g., protein kinases in cancer; Zhang, Yang, & Gray, 2009), NOD (nucleotide-binding and oligomerization domain)-like receptors (NLRs; Geddes, Magalhaes, & Girardin, 2009) of “omal” intracellular targets like the proteasome (Ruggeri, Miknyoczki, Dorsey, & Hui, 2009), the spliceosome (Rino & Carmo-Fonseca, 2009), and the inflammasome (Martinon & Tschopp, 2007) were not considered for many more years. Similarly proteostasis networks (Powers, Morimoto, Dillin, Kelly, & Balch, 2009), a fundamental role for mitochondrial dysfunction in disease etiology and drug treatment (Javadov et al., 2009, Kita et al., 2004, Wu et al., 2009), and the use of antibodies (Brekke & Sandlie, 2003) and RNA interference (Dykxhoorn & Lieberman, 2005) were/are all novel concepts for therapeutics. Additionally, until recently, disease causality was rarely considered in terms other than as a binary event. Thus, in the mid- to late twentieth century, the prevailing view was that diseases were caused by tissue dysfunction with the progression spectrum reflecting the difference between the normal and diseased state. That disease states could reflect an imbalance or overexpression of a normal homeostatic defense process, such as parainflammation (Medzhitov, 2008), was a concept that evolved over time. Molecular pharmacology thus added a new dimension to the drug discovery paradigm with the provision of a molecular basis for tissue dysfunction (Enna, Fuerstein, Piette, & Williams, 2008).

The mapping of the human genome provided an additional certainty to the molecular equation such that it was believed that defects in a single gene would be found responsible for a particular disease. This led to an explosion in gene association studies with common conditions like Parkinson’s disease, Type II diabetes, and hypertension being anticipated to be linked to a disease-specific gene variant that would be common to all those suffering from these conditions. However, once data were accumulated, unbridled optimism gave way to the realization that multiple factors, genetic and epigenetic, were usually causal for human disorders (Hardy and Singleton, 2009, Wilgenbus et al., 2007, Williams, 2009, Uher et al., 2009, Uher et al., 2009, Vogelstein and Hayden, 2008).

Nonetheless, the molecular era of drug discovery, and the focus on developing targeted therapeutics, has yielded many important new drugs, including the statins for hypercholesterolemia (Mills et al., 2008), β-adrenoceptor antagonists (Task Force, 2004), angiotensin-converting enzyme (ACE) inhibitors, calcium blockers (Neal et al., 2000), renin inhibitors (Villamil et al., 2007), and vasopressin V₂ antagonists (Miyazaki, Fujiki, Yamamura, Nakamura, & Mori, 2007) for hypertension, the SSRI (selective 5-HT reuptake inhibitor) antidepressants (Wong, Perry, & Bymaster, 2005), and the anxiolytic benzodiazepines (BZ) (Martin et al., 2007). While the selective cyclooxygenase (COX-2) inhibitors celecoxib, rofecoxib, and valdecoxib were withdrawn from the market because of an increased incidence of myocardial infarction and ischemic stroke associated with their use (Wong et al., 2005), these second-generation nonsteroidal anti-inflammatory drugs (NSAIDs) were highly effective as arthritis medications and had utility in the treatment of certain cancer types (Kashfi, 2009). Similarly, etanercept, infliximab, and adalimumab, biologics and antibodies that target the TNF-α receptor–ligand interaction, are important drugs for reducing the inflammatory consequences associated with rheumatoid, psoriatic and juvenile idiopathic arthritis, ankylosing spondylitis, and plaque psoriasis (Shealy & Visvanathans, 2008).

However, it is also noteworthy that many very useful medications, including clozapine for schizophrenia, pregabalin for neuropathic pain, modafinil for wake promotion, and valproic acid for epilepsy and biopolar disorder, have as yet no clearly defined molecular mechanism of action despite many years of research. Nonetheless, these compounds, through targets yet to be discovered or because of their non-selective interaction with multiple targets (Roth, Sheffler, & Kroeze, 2004), are effective medications. This reinforces the value of a more holistic, and perhaps a less target-oriented, approach to biomedical research like that traditionally embodied in the discipline of pharmacology.