This module will examine the research and development story of major classes of marketed ion channel drugs in the context of the critical technologies which enabled their discovery. Two examples which figure prominently in both modern cardiovascular medicine, and in the development of technology strategies for prosecuting ion channel targets broadly, are the quinidine class of Na+-channel blockers, and the dihydropyridine class of Ca++-channel blockers.
Na+ channel blocking anti-arrhythmic drugs only exhibit a tolerable therapeutic index due to their innate property of state-dependent binding to specific ion channels. Under hypoxia driven pathophysiological conditions in the heart, the under perfused areas of myocardium develop aberrant contractile rhythms driven by asynchronous high frequency firing of cardiac action potentials. Elegant electrophysiological measurements of Na+ channel activity in myocytes under such conditions demonstrated a much higher open probability relative to their Na+ channel counterparts in the myocytes of regions unaffected by hypoxia. Further studies revealed what we know now, that clinically utilized Na+ channel blocking agents bind with much higher affinity to Na+ channels in their open state relative to the closed state, and therein lies the explanation of why these drugs can be used clinically inhibit focal cardiac arrhythmias, while sparing the excitability and contractility of myocytes in healthy regions of the heart.
Dihydropyridine L-type Ca2+ channel blockers are safe and efficacious anti-hypertensive drugs because these molecules preferentially bind with by at least one to two orders of higher affinity to an inactivated conformational state of the L-type Ca2+ channels found in peripheral arterial smooth muscle cells due to their inherent depolarized resting membrane potential. On the other hand, L-type Ca2+ channels expressed in the heart cardiomyocytes spend most of their time in a non-inactivated conformational state, which does not bind dihydropyridine drugs with high affinity, and therein lies the clinically relevant therapeutic index of this class of ion channel modulator drugs.
Both of these examples underscore the point that "functional selectivity" of ion channel modulator drugs is not only possible, but is of enormous importance for the discovery & clinical development of future ion channel drugs. Secondly, these classical examples illustrate beautifully why it is critical to develop ion channel assays that allow full voltage & time dependent control over ion channel function in assay screening tiers. Without this ability, it is impossible to classify compounds by their relative rate or state dependence, and thus impossible to leverage functional selectivity to create safer drugs. A critical technology which provides discrete, micro-second scale command of membrane voltage in intact cells is patch clamp electrophysiology, and it is why this technology is critical to the characterization of ion channel drugs. A large technology landscape has grown around the core patch-clamp technique over the last 3 decades as drug discovery pursues new ion channel targets and novel mechanisms of action. In module 2 we will further explore the ion channel technology landscape, and how it has impacted the discovery of next generation ion channel drugs.
Dr. Ronald Knox is currently a Group Leader of Lead Evaluation & Ion Channel Technologies at Bristol-Myers Squibb (BMS) at their Wallingford site in Connecticut, USA. These groups are responsible for all of the high throughput in vitro lead optimization SAR assays for Neuroscience & Virology for BMS. Prior to joining BMS, he conducted post doctoral studies in the area of ion channel modulation at Yale University. Dr. Knox obtained his Bachelor of Science degree in Pharmacology at Glasgow University, Scotland and his Ph.D, studying opioid receptor regulation of nociceptive spinal neurotransmission at University College London, England.