Second Generation βββββ-Blockers (Selective βββββ 1 -Blockers)

5.2.2. Second Generation βββββ-Blockers (Selective βββββ 1 -Blockers)

The genesis of the selective βββββ 1 -blockers or the second generation βββββ-blockers received its legiti- mate cognizance by virtue of the stark reality that propranolol (see Section 12.5.2.1.A) happens to be a non-selective βββββ-antagonist that eventually acts as an antagonist at both β 1 -receptors and β 2 -receptors. Hence, it does give rise to a very serious problem if the patient suffers from ‘asthma’, because the very administration of propranolol (i.e., first-generation βββββ-blocker) would not only initiate but also pre-

cipitate an ‘asthmatic attack’ by sharply antagonizing the prevailing βββββ 2 -receptors in the bronchial smooth muscle. Ultimately, it would give rise to sudden contraction of bronchial smooth muscle followed by an eventual closure of the airways.

A typical example of a potent drug belonging to this particular class is practolol which shall be described as given below :

A. Practolol INN

N-[4-[2-Hydroxy-3-[(1-methylethyl)-amino] propoxy] phenyl] acetamide ; Eraldin (R) .

Coleman (1979)** synthesized for the first time a series of twelve para-acylphenoxyethanol-and propanolamines ; of which, only one of them, practolol, was subjected to both extensive and intensive clinical trials.

Practolol was found to be less potent than propranolol. It also exhibited intrinsic sympathomimetic activity (ISA) to a certain extent. It is pertinent to state here that one particular property not earlier observed with the β-blockers : the ability predominantly to inhibit isoproterenol (IPR)-induced tachy- cardia, while exhibiting a minimal or no effect on the IPR-depressor (i.e., hypotensive) response. In other words, practolol displayed cardioselectivity. Hence, for the first ever instance it was revealed and evidenced that the inhibition of β-adrenergic response may be confined significantly to certain sites.

Note. Practolol was eventually withdrawn due to relatively rare, but of course extremely serious

dermatologic as well as ophthalmic toxicological actions that ultimately led to total blindness and fatalities.

A comprehensive and intensive research of practolol was accomplished in a systematic manner, and it was proved amply that the ‘acetamido functional moiety’ had to be strategically located at the para position of the aromatic phenyl ring rather than the correpsonding ortho- or meta-positions if the

structure was to retain specifically the desired selectivity for the cardiac βββββ 1 -receptors. Fig. 13.1(a) and *Tachycardia (i.e., an abnormal rapidity of heart action, usually heart rate more, than 100 beats per minute in adults)

resulting from stimuli outside the heart, reflexly accelerating the heart-rate or depressing vagal tone. **Coleman AJ et al. Biochem. Pharmacol., 28, 10, 1979.

397 (b) evidently depicts that in the particular instance of para-substitution (practolol) there exists an extra

AUTONOMIC DRUGS

H-bonding interaction in the βββββ 1 -receptors but not the βββββ-receptors ; whereas, in the meta-substitution the above mentioned criteria (i.e., physical characteristic feature of an extra H-bonding interaction) is absolutely non-existence.

(a) Para-substitution (showing extra (b) Meta-substitution H-bonding interaction)

Fig. 13.1. (a) and (b) Bonding Interactions with βββββ 1 -Receptors.

[Adapted from : Patrick GL, An Introduction to Medicinal Chemistry, Oxford University Press,

Oxford UK, 2nd edn., 2001]

C HAPTER

Special Note. The subsequent replacement of the acetamido functional moiety with other groups that are certainly capable of hydrogen bonding ultimately gave rise to the synthesis of a series of highly specific cardioselective βββββ 1 -blockers that were eventually employed as potent drugs,

namely : Atenolol ; Betaxolol ; Metoprolol.