Celiprolol: Introduction

American Founded

Heart

Journal

in 1925

NOVEMBER

1988

Volume

116,

Number

6, Part

2

Celiprolol: Introduction Richard

Gorlin,

MD New York, N.Y.

There has been a profusion of Padrenergic-blocking agents available to the clinician. Whenever a new agent is introduced, there are certain conditions that must be met. The first and most obvious is for the retention of the favorable effects of previous Pblockers on cardiovascular disease. Second is the potential a new drug may have for diminished side effects inherent in the .&blocker class. Third is the introduction of a unique additive property apart from &receptor blockade, which extends the efficacy of the pharmacotherapeutic agent. Such agents From the Department of Medicine, Mount Sinai Medical Center. Reprint requests: Richard Gorlin, MD, Murray M. Rosenberg Professor of Medicine, Chairman, Department of Medicine, Mount Sinai Medical Center, New York, NY 10029-65’74.

HO-

-CH-CH,-NH-W

,3

Metoprolol (cardioselective

lsoproterenol (isoprenaline) (beta agonist)

-0-W-CH-CH2-NH-CH’

0

HOo=c’

‘CH3

b

Propranolol (non-cardioselective

beta receptor

’

,I0

C%

CY CH,-CH,-

NH,

Labetalol (combined cardioselective beta, and alpha, receptor blocker)

blocker)

\ 0

\ Ai

’

&i

\

\

blockerj

-Cl-l-CH,-NH-CH

-NH-C-N

Cl+,-;-NH-CH2-CH-CH,-OC%

beta, receptor

3

8 ‘3 I

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C”,

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0

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A”

must retain antianginal, antihypertensive, cardioprotective, and hypertrophy-regressive properties to have significant continuing value. A number of P-blockers (Table I) have shown improvements in issues of practicality or side effects, for example, an extended duration of action, reduced penetrance to the brain, or more constant modes of metabolism and excretion. An example of complementary properties is an agent such as labetalol, which theoretically acts as a strong &-selective blocker and a weak at-blocker. This is the context in which one must evaluate celiprolol. Its molecular structure, shown in Fig. 1, is compared with that of a P-agonist, nonselective and selective &blockers, and an a-receptor blocker. Celiprolol has been found to be an effective &blocker in coronary heart disease

W

H ,N ‘N-CH,/

C

\\

N-

‘cy C’H

’

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CELIPROLOL (cardioselectfve combined beta, and alpha, receptor and beta, receptor partial agonist)

blocker,

Fig. 1. Structural comparison of celiprolol with cardioselective ers, a-receptor blockers, and a P-receptor antagonist.

Phentolamine (alpha receptor

and nonselective

blocker)

&adrenoceptor block-

1383

November

Gorlin

Table

American

I.

Chemical

structure:

Different

types of adrenergic-

receptor blockers Isoproterenol (isoprenaline) (/!-agonist) Phentolamine (u-receptor blocker) Propranolol (noncardioselective @-receptor blocker) Metoprolol (cardioselective /3-receptor blocker) Labetalol (combined cardioselective fll- and n2-receptor blocker) Celiprolol (combined cardioselective /3- and cu,-receptor blocker and &receptor agonist)

and hypertension and to have a low side effect profile, long duration of action, and predominant renal excretion. Of great interest, however, is the fact that although this agent inhibits P,-adrenergic receptors, it also stimulates &receptors and weakly inhibits a,-receptors. There may also be direct actions on smooth muscle, aside from those medi-

The role of adrenoceptors metabolic regulation

Heart

1988 Journal

ated through the ,&receptors. The end result is to effect smooth muscle relaxation, as in the vasculature and bronchi pari passu with inhibition of the /3,-stimulatory action, particularly the myocardium. The potential offered by this unique molecular capability ranges from the ability to use a B-blocker in asthmatic patients and those with Raynaud’s disease, to its pluripotential actions to alleviate hypertension. Through vasodilation, as well as its direct cardiac actions, the concomitant reduction in afterload may make celiprolol unique in the proposed treatment of cardiomyopathy by P-receptor blockade. The purpose of this symposium proceedings is to explore the current status of this unusual pharmacologic agent in the management of cardiovascular disease and identify future directions for basic and clinical investigation of this potentially valuable new drug.

in circulatory

and

This survey covers the classification and subdivisions of OL- and ,&adrenoceptors, incktding (Y, and receptor subtypes, together with the distribution and a2, B, and &, and pre- and postsynaptic functional relevance of the various adrenoceptor subtypes. The emphasis will be on their relevance in circulatory regulatory processes, especially those of the blood vessels. The (Y- and @-adrenoceptor antagonists that interact with various receptor subtypes are briefly discussed. The control of a,-adrenoceptors concerned with blood pressure regulation is an important target for centrally acting antihypertensive drugs (such as clonidine or a-methyidopa). Changes in adrenoceptor density, particularly the down-regulation of &-adrenoceptors (but not &), are found in congestive heart failure. However, the experimental findings about a-and @-adrenoceptors in essential hypertension remain controversial. Finally, the influence of a’- and &adrenoceptor antagonists on plasma lipids and carbohydrate metabolism is briefly reviewed. The changes found may be only partly explained on the basis of (Y- or @-receptor blockade. (AM HEART J 1988;118:1384.)

Peter A. Van Zwieten, MD, PhD Amsterdam,

The Netherlands

Although it remained hypothesis until the 197Os, the concept of receptors as targets for both endogenous neurotransmitters and synthetic drugs has proved a

constructive working model. This has been of particular value not only to pharmacology but also to pathophysiology. The introduction of radioligandhinrlinz

From demic

the Division of Pharmacotherapy, Medical Center

Reprint requests: Peter A. Van Zwieten, py, University of Amsterdam, Academic Amsterdam 1105 AZ, The Netherlands.

1384

University

of Amsterdam,

MD, Division of PharmacotberaMedical Center, Meibergdreef

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15,

taphniqlro?

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129 TV q=roa&

the

concepts of receptors in a more coherent manner, almost allowing visualization of these receptors. More recently, we have become interested in the transfer of signals from activated receptors to the