02-Adrenoreceptors potency

In contrast, branching of the N-substituent often increases 6-adrenoreceptor potency and, in some instances 62 selectivity. 

Another example of marked B-adrenoreceptor potency enhancement by N-substltution is illustrated by fenoterol (60a). which is strikingly more potent than its N-tert-butyl counterpart, ter-butallne (6. Fenoterol is a clinically effective bronchodilator by either oral or aerosol administration however, some cardiac stimulation and tremors are noted (136, 137). Cat soleus muscle, bronchial and heart rate experiments indicate selective B2 adrenoreceptor potency for 60b (138). Another resorcinol, one of a series of xanthine derivatives, is reproterol (60c). Repro-terol is clinically effective in bronchial asthma it causes minimum CNS and cardiovascular side effects upon administration orally or by inhalation, and tachyphylaxis is not observed (139). 

Pharmacology Carvedilol, an antihypertensive agent, is a racemic mixture in which nonselective -adrenoreceptor blocking activity is present in the S(-) enantiomer and -adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity. 

Adrenoreceptors were initially characterized pharmacologically, with receptors having the comparative potencies epinephrine > norepinephrine >> isoproterenol, and receptors having the comparative potencies isoproterenol > epinephrine > norepinephrine. The development of selective antagonists revealed the presence of subtypes of these receptors, which were finally characterized by molecular cloning. We now know that unique genes encode the receptor subtypes listed in Table 9-1. 

The compound bearing an A, A -dimethyl-1,6-hexane-diamine moiety (2) was the most active of the series, being more potent than prazosin (Giardinh et al., 1989). The chain length effect on potency allowed us to postulate that the rat vas deferens a,-adrenoreceptor incorporates a lipophilic area, located between the binding sites for the quinazoline and the furan rings of prazosin, which can optimally accommodate an hexane spacer. 

Similarly to the trend observed at aj -adrenoreceptors, stereoisomers (-)-31, (-l-)-31, (-)-32 and ( + )-32 displayed a radioreceptor binding affinity higher than that observed in functional assays at 5-HT, receptors. Furthermore, the eudismic ratio between (-)-31 and ( + )-31 enantiomers was identical to that observed in functional assays whereas for (- )-32 and (-I- )-32 it was much lower. However, a difference in potency observed for the agonists... 

Melchiorre, C., Brasili, L., Giardina, D., Pigini, M Strappaghetti, G., 1984. 2-[[[2-(2,6-Dimethoxyphenoxy)ethyl]amino]methyl]-1,4-be-noxathian a new antagonist with high potency and selectivity toward a I-adrenoreceptors. J. Med. Chem. 27, 1535-1536. 

The sulfamlde has B-adrenoreceptor stimulant potency intermediate between the ethyl (18) and isopropyl (19) carbani-lates. ... 

Substitution of the sulfonyl group also affects adrenergic activity. In general, as noted in related series (Table I), B-adrenoreceptor agonist potency decreases as the size of the sulfonyl-substituent is increased. Thus, in the guinea pig tracheal test the methyl derivative sulfonterol is three to... 

The racemic phenoxymethylimidazoline lofexidine (44) is unusual among the imidazolines in having a2-adrenoreceptor agonist activity it is used as an antihypertensive and is similar in potency to clonidine (133) [52]. The route of preparation is shown in Scheme 5.12. Resolution of (44) with (-)-dibenzoyltartaric acid gave the enantiomers levlofexidine [(-)-lofexidine] (52) and dexlofexidine [(+)-lofexidine] (53) [53]. 

Bufuralol is a nonselective (3-adrenoreceptor blocking agent of comparable potency to propranolol. It has proven to be effective in treating hypertension and is a potent nonselective p-adrenergic receptor antagonist. Similarly to the method described earlier in Scheme 57.9, an efficient chemoenzymatic synthesis of (/ )-bufuralol has been reported involving a DKR of the chlorohydrin key intermediate rac-44 (Scheme 57.10). ... 

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