The β‐adrenoceptor blocking properties of the α‐methyl analogues of propranolol and practolol in the anaesthetized dog

Abstract

Summary1. The /8-adrenoceptor blocking properties of a-methyl propranolol and a-methyl practolol were determined in anaesthetized dogs according to their abilities to modify the isoprenaline-induced effects on diastolic pressure, heart rate, myocardial contractile force, femoral arterial blood flow and pulmonary airway resistance. 2. a-Methyl propranolol shifted the isoprenaline dose-response curves for the fall in diastolic pressure and the positive inotropic and chronotropic responses to the right in a parallel manner yielding pA2 and slope values of 6'66 (092), 6-34 (0 77) and 6-59 (0-61) respectively. The slopes of the graphs for determining pA2 values for the cardiac p-adrenoceptor blocking properties of amethyl propranolol were significantly less than 1 and indicated a mechanism other than simple, competitive, reversible antagonism. 3. a-Methyl propranolol exerted a much weaker blockade of respiratory smooth muscle /8-adrenoceptors than has been reported for propranolol.

The SELECTIVITY OF Β‐ADRENOCEPTOR ANTAGONISTS ON CARDIOVASCULAR AND BRONCHODILATOR RESPONSES TO ISOPRENALINE IN THE ANAESTHETIZED DOG

“…For example, it is not possible to control the distribution and disposition patterns of the administered drugs. Conclusions from the above publications are further complicated because some of the antagonists used had only low potency in the tissues concerned (Levy, 1973c;Wasserman & Levy, 1974) or because some results were inconsistent with competitive antagonism (Boissier et aL, 1971). With these potential drawbacks in mind, it is appropriate to consider the relevance of the present results to the sub-classification of 1-adrenoceptors.…”

The ANTAGONISM BY PROPRANOLOL AND Α‐METHYLPROPRANOLOL (ICI 77602) OF VASCULAR AND CARDIAC RESPONSES TO ISOPRENALINE IN ANAESTHETIZED DOGS

“…a-Methylpropranolol was more potent in antagonizing vascular (hind limb perfusion pressure) than cardiac (heart rate) responses to isoprenaline in dogs, and on this basis it could be classified as a vascular-selective or Pz-adrenoceptor antagonist, along with H 35/25 and a-methyl DCI. At first sight, this appeared tosupport the conclusion of Levy (1973), that a-methylpropranolol was a selective 0-adrenoceptor antagonist. However, inspection of the pA2 values of 6.66 for vascular (diastolic blood pressure) and 6.59 for cardiac (heart rate) responses to isoprenaline quoted by Levy (1973) reveals no support for vascular cardiac selectivity.…”

“…At first sight, this appeared tosupport the conclusion of Levy (1973), that a-methylpropranolol was a selective 0-adrenoceptor antagonist. However, inspection of the pA2 values of 6.66 for vascular (diastolic blood pressure) and 6.59 for cardiac (heart rate) responses to isoprenaline quoted by Levy (1973) reveals no support for vascular cardiac selectivity. More importantly in the present study, propranolol itself was more potent in antagonizing vascular than cardiac responses to isoprenaline.…”

“…l), the a-methyl-substituted analogue of propranolol. At the time this study commenced (O'Donnell & Fitzgerald, 1973), none of the properties of this drug had been described: since then, Levy (1973) has described some of itsp-adrenoceptor blocking properties in anaesthetized dogs. Levy (1 973) suggested that a-methylpropranolol was a more selective blocking drug than propranolol but, in drawing this conclusion, he placed more emphasis on respiratory cardiac selectivity than on vascular cardiac selectivity.…”

A STUDY OF SOME PROPRANOLOL ANALOGUES FOR SELECTIVE β‐ADRENOCEPTOR ANTAGONISM USING pA2 VALUES ON ISOLATED TRACHEA AND ATRIA FROM GUINEA‐PIG

“…Two of the antagonists examined were benzimidazole analogues of propranolol (Figure 1), the synthesis of which has been recently described (Fauland, Kampe, Thiel, Bartsch & Schaumann, 1976;Crooks, Wright, Callery & Moreton, 1979). Crooks and his co-workers suggested that one of these compounds, which they referred to as 4-BIP (+ )-1-(4-benzimidazoloxy)-3-isopropylamino-2-propanol (Figure 1), was a potent selective f2-adrenoceptor antagonist which they deduced from 0007-1188/80/040705-06 $01.00 (Levy, 1973;Todd, 1976;Fitzgerald & O'Donnell, 1978). In the present study an attempt has been made to quantify the selectivity of this antagonist in vitro.…”