DRUG-RECEPTOR RELATIONSHIP FOR VALSARTAN (AND LISINOPRIL)

Molecular Pharmacology Final Presentation by Tin Ho

(cc) Tin Ho 2012

The Protagonists

Generic name(Trade name)

Lisinopril (Prinivil, Zestril)

Valsartan(Diovan)

Indications Hypertension,congestive heart failure, heart attacks.

Hypertension,congestive heart failure, post-myocardial infraction

Off-label N/A Alzheimer, Dementia

Class of drug ACE Inhibitor ARBSimilar drugs Enalapril, benazepril,

quinapril, moexipril, ramipril, trandolapril, perindopril.

Sartan family:Losartan, telmisartan, olmessartan medoxomil

Reason for selection Family member takes it “Work made me take it”

Basic Chemical Properties

Durg Prinivil (Lisinopril) Diovan (Valsartan)Original Manufacturer

Merck Novartis

Generic Manufacturer

Sandoz, Ivax, Vintage… None yet.Patent expires 2012

Molecular Formula C21H31N3O5 C24H29N5O3

Molecular Weight 405.22 435.22Chemical Structure

Drug TypesGeneric name(Trade name)

Lisinopril (Prinivil, Zestril)

Valsartan(Diovan)

Class of drug Non-sulfhydryl Angiotensin-converting-enzyme inhibitor (ACE-I)

Angiotensin receptor blocker (ARB)

Agonist or antagonist? Antagonist.Inhibit enzyme action, inactivate enzyme.

Antagonist*. Blocks AT1 receptor.

Kind of receptor affected

Enzyme inactivation due by 3D structure change induced by drug binding.

Angiotensin II receptor type 1 (AT1), a G-protein coupled receptor central to the Renin-Angiotensin System.

What Affects Blood Pressure?

http://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png

Main Fate of AngII

D-R-V-Y-I-H-P-F-H-L | V-I...Keep the first 10 AA

D-R-V-Y-I-H-P-F | H-LUse only the first 8 AA

D-R-V-Y-I-H-P-F-H-L-V-I-...452 AA long protein

Where the drugs acts?

AT2

Mode of Action• Angiotensin II Receptor Type 1 is a 7TM/GCPR

Cross

talk

Adapted from Dr Picones Molecular Pharmacology Lecture Slides 2012.

Effects of AngII

NE = norepinephrine; CNS = Central Nervous System

Collateral Consequences

• ACE-I will reduce AngII by blocking its production• ARB will INCREASE AngII in circulation by blocking their

“docking station”.

ARB’s Side Effects• Blood pressure regulation is part of a large RAAS system.• AT1 receptors have many subtypes with wide array of

effects.• Side effects are therefore very possible.

• Overall, well tolerated. • Angioedema, cough. Typical of ARB, and less severe than ACE-I• Teratogenic potential do not use in pregnancy.• Hypotension, oliguria, progressive azotemia, or acute renal failure may

develop for patients with renal artery stenosis and related illness.• Hyperkalemia may develop for patients with renal disease or altered

K+ diet.• ARB enhances other blood pressure lowering meds dosage

adjustment.

At this point, I will let Rohan give a brief talk about the effect of the following molecule on the brain:

 

 

 Discussion will now turn to the experimental assays of

drug-receptor activities (for Valsartan only)

ZZZ ???

Valsartan dose-response plots3H-Valsartan vs AngII binding in recombinant AT1 receptor in CHO

Verheijen, I., Fierens, F. L., Debacker, J. P., Vauquelin, G. and Vanderheyden, P. M. (2000) Interaction between the partially insurmountable antagonist valsartan and human recombinant angiotensin II type 1 receptors. Fundam. Clin. Pharmacol., 14: 577-585. [PMID:11206708]

CHO w/ AngII 30min pre-incubation0 valsartan0.5nM valsartan 5nM valsartan50nM valsartan

AngII co-incubation0 vs 50 nM valsartan

Concentration-inhibition curve of valsartan

Verheijen, I., Fierens, F. L., Debacker, J. P., Vauquelin, G. and Vanderheyden, P. M. (2000) Interaction between the partially insurmountable antagonist valsartan and human recombinant angiotensin II type 1 receptors. Fundam. Clin. Pharmacol., 14: 577-585. [PMID:11206708]

Valsartan binding is reversible, and high conc of AngII will displace some valsartan, inducing IP accumulation.Conclusion: Valsartan is a competitor to AngII on AT1 Valsartan acts as antagonist

30 min pre-incubate:10 uM AngII0.1 uM AngII

CHO w/ valsartanCo-incubate 10 uM AngII

% Receptor Occupancyirbesartan > valsartan > losartan

Clinical Pharmacology & Therapeutics (1999) 66, 367–373; doi: 10.1053/cp.1999.v66.a101162Rad

iore

cept

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ssay

Diastolic Blood Pressureirbesartan > valsartan > losartan

Clinical Pharmacology & Therapeutics (1999) 66, 367–373; doi: 10.1053/cp.1999.v66.a101162

[Valsartan] vs BP• Valsartan works. This ARB is an antagonist.

New Discovery (in 2008)• Reported in Molecular Endocrinology by Miura S et al.

(associated with Novartis).• Some ARB such as Valsartan and Omesartan act as

inverse agonists...

Dr Picones Molecular Pharmacology Lecture Slides 2012.

Wild type AT1 has basal activity

Inc AT1 expression

• Use mutants AT1 that amplify Drug-Receptor binding• N111G, F77A have high basal IP production, with significant decrease when

Valsartan is added

Mutated AT1 shows inverse binding potential of Valsartan

• Lysine199, Serine105, Serine109 mutations drastically change Valsartan binding to AT1, while Bmax is little changed

3D ModelsValsartan (small molecule drug)

7TM/GPCR

Angiotensin II (8 AA peptide)

Losartan, has no inverse agonist activity

©2008 by Endocrine Society

Valsartan binding to Lys199 stabilizes inactive form of AT1

Summary• Valsartan size is similar to the AngII peptide hormone and

competes with it for the binding site of AT1 receptor.• AT1 is a GPCR/7TM receptor with basal level of Inositol

Phosphate production.• Valsartan binding to AT1 lowers its basal activity by

stabilizing the receptor, it is an inverse agonist.• These findings would not be possible w/o the tools of

molecular pharmacology.

• (Lisinopril is a inhibitor to the enzyme – Antagonist)

Sources• Wikipedia• Dr Picones Molecular Pharmacology Lecture Slides 2012• Eric Fisher Presentation on inverse agonist

http://mcb.web.psi.ch/teaching/Signalling/Presentations_0809/GPCR_Fischer.pdf

• Verheijen, I., Fierens, F. L., Debacker, J. P., Vauquelin, G. and Vanderheyden, P. M. (2000) Interaction between the partially insurmountable antagonist valsartan and human recombinant angiotensin II type 1 receptors.

• Fundam. Clin. Pharmacol., 14: 577-585. [PMID:11206708] • Clinical Pharmacology & Therapeutics (1999) 66, 367–373; doi:

10.1053/cp.1999.v66.a101162• JL Pool et al. Dose-response efficacy of valsartan, a new angiotensin II

receptor blocker. Nature. http://www.nature.com/jhh/journal/v13/n4/pdf/1000788a.pdf

• Miura S et al. Molecular Endocrinology 2008;22:139-146• Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12 th

Ed.

Thank You!

I am riding 545 miles to fundraise for the SF AIDS Foundation. Visit my page at http://www.toFightHIV.org/goto/tin- Tin Ho

BACKUP SLIDES

MoA ARB (Valsartan)• Valsartan belongs to the group of ARB.... Which block AT1 receptor, thereby interfering with

normal action of Angiotensin peptide. This fits the definition of “antagonist”. (use diagram and just explain these instead of word here)

• Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main uses are in the treatment ofhypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure.

• Mechanism of action• These substances are AT1-receptor antagonists – that is, they block the activation of 

angiotensin II AT1 receptors. Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, amongst other actions. The combined effect reduces blood pressure.

• The specific efficacy of each ARB within this class depends upon a combination of three pharmacodynamic and pharmacokinetic parameters. Efficacy requires three key PD/ PK areas at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter are at variance now.

NaG&G 26-7.

Salt level directly affect blood pressure.

Inhibition of the renin-angiotensin system will cause a large drop in blood pressure in Na+-depleted individuals.

when ACE-I is used(not sure why Renin yet).Renin ultimately affects AngII formation.

No longer needed

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• Criscione, L., de Gasparo, M., Buhlmayer, P., Whitebread, S., Ramjoue, H. P. R. and Wood, J. (1993) Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin-II AT1- receptor subtype. Br. J. Pharmacol., 110: 761-771. [PMID:8242249]

Adverse Effects• Drugbank.ca also list several drug interactions... But previously reported as “not likely”

• Adverse Effects. ARBs are generally well tolerated. The incidence of angioedema and cough with ARBs is less than that with ACE inhibitors.

• As with ACE inhibitors, ARBs have teratogenic potential and should be discontinued in pregnancy.

• In patients whose arterial blood pressure or renal function is highly dependent on the RAS (e.g., renal artery stenosis), ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure.

• ARBs may cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics.

• ARBs enhance the blood pressure–lowering effect of other anti-hypertensive drugs, a desirable effect but one that may necessitate dosage adjustment.

• There are rare postmarketing reports of anaphylaxis, abnormal hepatic function, hepatitis, neutropenia, leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia, alopecia, and vasculitis, including Henoch-Schönlein purpura.

• Pregnacy, don’t take ARB• (avoid? Or monotor?) Renal patients • (vs ACE-I?)

Angiotenism Peptide• Angiotensinogen• Angiotensinogen is an α-2-globulin that is produced

constitutively and released into the circulation mainly by the liver.

• Angiotensinogen is also known as renin substrate.• Human angiotensinogen is 452 amino acids long. The first

12 amino acids are the most important for activity.• Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-...• Angiotensin I• Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-...• Angiotensin II• Asp-Arg-Val-Tyr-Ile-His-Pro-Phe | His-Leu

AT1 downstream• Need to find pathway of AT1 to vasodilation...

• Lisinopril pathway: http://pathman.smpdb.ca/pathways/SMP00150/pathway?reset=true&highlight%255bP30556%255d=true

• Valsartan pathway:• http://pathman.smpdb.ca/pathways/SMP00165/pathway

• http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=34

• Seems to have lot of good link info. Eg

• And • http://

www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=6

Functional Assays

Ang II-induced aldosterone release

Species:  Human

Tissue:  bovine adrenal glomerulosa cells

Response measured:  Aldosterone releaseReferences:  28

• Guide to pharmacology• http://

www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=6

• Some reading list...• Lot of basic fact about drug, similar to drugbank... Has

xlogp pKi and radioligands Kd info... (well, link, not sure have info).

• http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+137862-53-4

• Molecular bio db, may lead to some relevant papers

• ACE Inhibitors inhibit conversion of AngI to active AngII. • Inhibition of AngII production lower blood pressure and

enhance natriuresis.• The left hand pathway indicates that ACE is used in

many pathway. ACE-I would inc Bradykinin, which in turn stimulates prostaglandin biosynthesis. This may also be part of the effect how ACE-I works.

• Lisinopril is ACE-I• Valsartan is ARB.• (G&G loc 29906 ch 26)

• G&G fig 26-8 • Also see caption of fig 26-10.• ARBs … more effective than ACE-I in reducing activation

of AT1.

• http://www.medscape.com/viewarticle/487957_3• Medscape news article with some plot of valsartan and

blood pressure.• Seems to be written for physician, digest of some papers??

• Next page maybe adverse reactions.

The Makers

Prinivil (Lisinopril) Diovan (Valsartan)Original Manufacturer Merck NovartisApproval date Dec 29, 1987 Dec 23, 1996 (capsule)

Jul 18, 2001 (tablet)Generic Manufacturer Sandoz, Ivax, Vintage… (Patent expires 2012)Generic approval date Jul 1, 2002 Oct 25, 2007 (tentative)Price – brand name $1.22/tablet $2.33/tabletPrice – generic Target $4/30days supply N/A

Adverse effects• The most commonly reported clinical adverse events with ARBs are

dizziness, headache, and fatigue, which are no different than placebo-treated patients. Cough or angioedema are rare with the use of ARBs in contrast to ACEIs, and ARBs can be used as an alternative to ACEIs for patients who develop cough without angioedema. With respect to the metabolic adverse events, mild hypokalemia (K+ <3.5 mEq/L), hyperuricemia, and hyperglycemia occurred in about 4.5% of patients on combination therapy with valsartan/HCTZ, mostly with the higher doses of HCTZ. Valsartan, like other ARBs, is metabolized by the cytochrome P450, but has modest affinity for the isoenzyme and is less likely to cause significant drug interactions.[21] Coadministration of ARBs with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, indomethacin, or warfarin produce no clinically significant pharmacokinetic interactions.

Thank You!

I am riding 545 miles for a fundraiser.  Please consider a donation to the SF AIDS foundation: http://www.toFightHIV.org/goto/tinNo donation is too small! -Tin Ho