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A CASE STUDY IN ION CHANNEL DRUG DISCOVERY

A CASE STUDY IN ION CHANNEL DRUG DISCOVERY. The group of drugs known as the “calcium channel blockers” or “calcium channel antagonists” provide an interesting case study from two perspectives: 1. As a mature group of therapeutics agents why are they cardiovascular selective?

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A CASE STUDY IN ION CHANNEL DRUG DISCOVERY

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  1. A CASE STUDY IN ION CHANNEL DRUG DISCOVERY The group of drugs known as the “calcium channel blockers” or “calcium channel antagonists” provide an interesting case study from two perspectives: 1. As a mature group of therapeutics agents why are they cardiovascular selective? 2. Given that there are several classes of voltage-gated calcium channels why has it been so difficult to find blockers active at the non-L-type channels?

  2. Classification of Voltage-Gated Ca2+ Channels Channel Class Nomenclature T L N P/Q R Sequence, CaV 3.1-3.3 1.1-1.3 2.2 2.1 2.3 Current IT IL IN IP/Q IR Conductance, pS 5-10 25 20 10-20 – Activation threshold low high high high high Inactivation rate fast slow moderate rapid – Permeation Ba2+>Ca2+ Ba2+>Ca2+ Ba2+>Ca2+ Ba2+>Ca2+ Ba2+=Ca2+ Function and Cardiac SA node, E-coupling in muscle, --------neurons only-------- Location neurons, endocrine cells, neurotransmitter release repetitive spiking, neurons spike activity Pharmacology: Blockers mibefradil nifedipine w-CTXGVIA w-AGAIVA ---- flunarizine verapamil kurotoxin diltiazem Agonists BayK 8644 Subunit Composition a1G, a1H, a1I a1S, a1C, a1D a1B a1A a1E (a subunits only) a1F

  3. Cardiovascular Selectivity of Ca2+ Antagonists Antagonist Ratio IC50 heart/IC50 vessel Diltiazem ~1 Verapamil ~1 Nifedipine ~10 Amlodipine ~10 Felodipine, Isradipine Nitrendipine, Nicardiine, ~100 Lacidipine Nisoldipine ~1000 Godfraind et al., 1992

  4. Selectivity of Action of 1,4-Dihydropyridines

  5. Differences Among 1,4-Dihydropyridines • Exist • Have mechanistic bases: • Pharmacokinetics • Channel type • Channel subtype • State-dependence • Contribute to: • Slow onset and offset of action • No activation of neurohormonal axis • Absence of negative inotropism • Vascular selectivity • Confirms therapeutic advantage Triggle, 1997

  6. A SUCCESS STORY THE DEVELOPMENT OF DRUGS ACTIVE AT THE L-TYPE CHANNEL MAY THUS BE REGARDED AS A SCIENTIFIC, CLINICAL AND COMMERCIAL SUCCESS. BUT THERE ARE MANY MORE CALCIUM CHANNEL TYPES………………

  7. L….. IS FOR LESSON • LESSONS TO BE LEARNED • The world is old • The world is gray • The lessons of life • Can’t be learned in a day • bob dylan

  8. OR…………….. If it worked for L then why not for T, N, P/Q, R and all the rest of the VGCC family?

  9. CURRENT TARGETS • CARDIOVASCULAR DRUGS • PAIN • NEURONAL ISCHEMIA AND STROKE • EPILEPSY

  10. T-CHANNEL BLOCKERS IN HYPERTENSION • Mibefradil: ( Posicor, Ro 40-5967 ) introduced as a novel antihypertensive/antianginal calcium channel antagonist. • Had initial favorable therapeutic and side-effect profile. • Withdrawn because of P450 interactions

  11. MIBEFRADIL • Chemically distinct from other classes • Blocks T-type channels • Non-selective: also blocks L-type channels at ~10 x higher concentration • Also blocks other HVA calcium channels • Cannot be used as an index of T channel function. Heady et al.,Jap. J. Pharmacol. 85: 339 (2001) Perez-Reyes, Physiol. Rev. 83: 117 (2002).

  12. CLINICAL BENEFITS OF T-TYPE CALCIUM CHANNEL BLOCKERS • No reflex tachycardia • Lack of negative inotropic effect • Potent coronary vasodilation • Minimal neurohormonal activation • Potent antihypertensive and antianginal effects • Reduces bp and hr without affecting cardiac contractility

  13. OTHER T-CHANNEL BLOCKERS • Many other classes: 1,4-dihydropyridines Antiepileptics ( phenytoin, barbiturates, ethosuximide, valproic acid ) Anaesthetics Antipsychotics • None are selective.

  14. PAIN TARGET VALIDATION • N-Type selective ziconotide and AM 336 are effective….but… • CaV2.1(a1B) KO’s have reduced response to neuropathic and inflammatory pain • b3 KO’s have reduced response to inflammatory pain • CaV2.2 and a2d up-regulated in some pain models • a2d binding site for gabapentin

  15. BUT………. • N-Type channels widely distributed: • side effects likely • CaV2.2 deficits include – • reduced baroreceptor reflex • reduced positive inotropic response • elevated bp and hr • Other calcium channels involved in pain: • CaV2.3 KO’s have reduced response to • inflammatory pain ( and impaired glucose met • CaV3 – mibefradil effective in mechanical and • thermal pain

  16. EPILEPSY TARGET VALIDATION • CaV3.1 KO’s resistant to absence seizures • Ethosuximide class of anti-epileptic drugs acts at T-type channels • CaV2.1 and CaV2.2 mutations linked to absence seizures and generalized epilepsy in mice • a2d2 mice (“ducky”) have generalized epilepsy • Mutant b4 subunit in lethargic epileptic mice

  17. STROKE AND NEURONAL ISCHEMIA • Everything works in animal models • Nothing works in human stroke • DeGraba and Pettigrew, Stroke 19: 475, 2000: Ovbiagele et al., Current Neuronal and Neuroscience Reports 3: 9, 2003. • WHY??? • Homogeneity of animal models • Timing of therapy in clinical conditions • Negative animal data not reported • Multiple pathways involved in clinical scene

  18. “….antiarrhythmic drug development strategy has slowly begun to evolve from a search for SELECTIVE ion channel agents to agents that exhibit MULTIPLE pharmacological actions in cardiac tissue”. • Pugsley, Drug Dev Res 55: 3, 2002.

  19. FROM THE MAGIC BULLET TO THEMAGIC SHOTGUN • Clozapine and other atypical antipsychotics • Imipramine and other tricyclics • ACE inhibitors • Matrix metalloproteinase inhibitors • Dopamine2 receptor antagonists • Amiodarone Morphy et al, DDT 9: 641, 2004; Roth et al., Nature Rev.Drug Disc. 3: 353, 2004

  20. LESSONS FROM L-TYPE CHANNELS • Discovered in absence of any structural or functional knowledge of the L-type calcium channel • Discovered using biological assays with direct and readily observable relationship to therapeutic goal – a well defined phenotype corresponding to L-type channel • Cardiovascular system dominated by the CaV1 class of channel • The several structural classes of calcium channel blockers all have prominent state-dependent binding properties. • Subtype pharmacology of little significance

  21. THE QUESTION Given 20+ years of failure is it still worth pursuing new voltage-gated calcium channel drugs?

  22. NEW TARGETS • 1. FERTILITY • 2. 02-SENSITIVE CHANNELS • 3. CHANNEL SUBUNIT BLOCKERS • 4. Ca2+ CHANNEL ACTIVATORS

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