Adrenergic agents. 4. Substituted phenoxypropanolamine derivatives as potential .beta.-adrenergic agonists

Abstract

A series of 1-(substituted phenoxy)-3-(tert-butylamino)-2-propanols in which the ring substituents were 3,4-dihydroxy (6f), 3- and 4-hydroxy (6g and 6h, respectively), 3-hydroxy-4-methylsulfonamido (6i), its 3,4-transposed isomer (6j), and 4-methylsulfonylmethyl (6k) was prepared and examined for beta-adrenergic agonist and/or antagonist properties. Two of these compounds, 6f and 6j, were potent beta-adrenoreceptor agonists in in vitro tests that measure a compound's ability to relax guinea pig tracheal smooth muscle and to increase the rate of contraction of guinea pig right atria. Several compounds had a dose-dependent effect. Although they produced potent beta-adrenergic agonist activity at low concentrations, 6g, 6h, and 6j antagonized the effects of a standard beta-adrenoreceptor agonist at higher concentrations. The methylsulfonylmethyl derivative 6k produced beta-adrenergic blocking effects as demonstrated by attenuation of isoproterenol-induced increases in the rate of contraction of an isolated rabbit heart preparation. On the basis of these pharmacological results, coupled with NMR spectral data, it appears that the previous suggestion that aryloxypropanolamines interact with beta-adrenocreceptors as a consequence of their ability to assume an orientation in which the benzene ring the ethanolamine moieties can be superimposed on those of corresponding adrenergic phenylethanolamines is invalid. An alternative "bicyclic" rigid conformation involving two intramolecular hydrogen bonds in the protonated form of the aryloxypropanolamines is suggested to account for the similar beta-adrenoreceptor activity of these compounds and related phenylethanolamines.

AGONISTIC AND ANTAGONISTIC ACTIONS OF 3,4‐DmYDROXY‐SUBSTITUTED PHENOXYPROPANOLAMINES DM GUINEA‐PIG ATRIA AND TRACHEA

“…The results obtained by Kaiser et al (1977) using OM-N-t-butylnoradrenaline in guineapig atrial and tracheal preparations are in general agreement with those found in the present study. In contrast to the present results obtained with OM-isoprenaline in guinea-pig atria and in the cat heart in vivo (Dowd et al, 1977), Casagrande et al (1973) found that the compound was a partial agonist in rabbit atrial preparations.…”

Structure of 2-hydroxy-3-isopropylaminopropyl 3,4-methylenedioxybenzoate hydrochloride

“…To explain the similar pharmacological activity of the two classes of drugs, several hypotheses have been advanced (Ariens, 1967;Dangoumau, Barrans & Cotrait, 1973;Cromer, 1970;Barrett, 1972;Kaiser, Jen, Garvey, Bowen, Colella & Wardell, 1977;Ammon, Howe, Erhardt, Balsamo, Macchia, Macchia & Keefe, 1977;Ammon, Balsamo, Macchia, Macchia, Howe & Keefe, 1975;Petrongolo et aL, 1977;Macchia, Macchia & Martinelli, 1980;Lrvgren, Hedberg & Nilsson, 1980) on the mechanism through which the CH2-O-Ar portion of the class (II) agents can substitute for the single aromatic moiety (Ar) of the class (I) compounds in the drug-receptor interaction. On the basis of the observation that the insertion of the CH2-O group modifies the distances between the Ar group and the other active centers of the drug, it had been proposed (Ariens, 1967;Dangoumau et al, 1973) that complementary additional receptor areas could be involved in the drug-receptor interaction.…”

New Aspects of β-Adrenergic Bronchodilator Drugs

“…Thus, oxypropanolamines have potent 3i-adrenoreceptor agonist or antagonist (168, 169) selectivity provided they have the absolute stereochemistry S (33,169). This is the same relative spacial orientation of the aromatic ring, hydroxy1 and amino groups found in the active adrenergic R-phenylethanolamines.…”

“…Several other catechols and related compounds with 3-adren ergic agonist activity involve a more profound structural modifi cation of the phenylethanolamine skeleton. The catecholoxypropanolamine 65^ which might be viewed as a congener of N-tertbutylnorepinephrine in which a 00Η 2 group is inserted between the catechol nucleus and the ethanolamine side chain, is a very potent 3-adrenoreceptor agonist; however, it has a marked selec tivity for cardiac rather than tracheobronchial muscle (33).…”

“…Further, quantum mechanical calculations indicate that the conformations of these classes of adrenergic agents obtained by X-ray diffrac tion are actually privileged ones (185). These suggestions, however, fail to rationalize the observation that similar modifi cations of the catechol ring of phenylethanolamines and phenoxypropanolamines induce a comparable change in 3-adrenoreceptor activity (33). To explore the possibility that these two differ ent classes might share a common ground-state conformation as an essential structural feature that satisfies the specific steric Downloaded requirements for the receptor loci of interaction an NMR confor mational analysis of some aryloxypropanolamines was performed (34).…”