Functional properties of atypical β-adrenoceptors on the guinea pig duodenum
Introduction
Atypical β-adrenoceptors have been identified by functional, molecular cloning and receptor binding studies in several gastrointestinal tract (for review see Manara et al., 1995) and adipose tissues (for review see Arch and Kaumann, 1993). Since this β-adrenoceptor subtype possesses an unusually low affinity for the typical β-adrenoceptor antagonists including propranolol, these receptors have been termed atypical β-adrenoceptors.
Recently, we have suggested that atypical β-adrenoceptors were involved in mediating the relaxant response of the guinea pig duodenum (Horinouchi and Koike, 1999a). We also demonstrated that the relaxant responses to catecholamines ((−)-isoprenaline, (−)-noradrenaline and (−)-adrenaline), to a selective β3-adrenoceptor agonist, BRL37344 ((R*, R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium salt), and to the non-conventional partial β3-adrenoceptor agonist, (±)-CGP12177A ((±)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride), were resistant to blockade by the non-selective β1- and β2-adrenoceptor antagonist, (±)-propranolol (1 μM) (Horinouchi and Koike, 1999a). However, the relaxant responses to the five agonists were competitively antagonized by a non-selective β1-, β2- and β3-adrenoceptor antagonist, (±)-bupranolol (Horinouchi and Koike, 1999a), although at concentrations greatly exceeding those required for β1- or β2-adrenoceptor blockade (Kaumann, 1989).
The atypical β-adrenoceptor-mediated responses are characterized by low stereoselectivity ratios of antagonist enantiomers Zaagsma and Nahorski, 1990, Emorine et al., 1994, while both β1- and β2-adrenoceptors exhibit high stereoselectivity (for review see Ruffolo, 1991). However, the isomeric activity ratio of trimetoquinol (the selective β2-adrenoceptor agonist) isomers in atypical β-adrenoceptors of rat esophageal smooth muscle was greater than that obtained in β1-adrenoceptors of rat atria and β2-adrenoceptors of rat trachea (Lezama et al., 1996). Trimetoquinol is a prototype of the tetrahydroisoquinoline class of compounds that is structurally distinct from catecholamines (Lezama et al., 1996). It lacks the β-hydroxyl group of catecholamines and the asymmetric carbon atom is contained within a semirigid tetrahydroisoquinoline ring (Lezama et al., 1996). It is possible that the isomeric activity ratio of stereoisomers at atypical β-adrenoceptors depend on the position of asymmetric carbon atom.
(±)-Propranolol, (±)-alprenolol, (±)-pindolol, (±)-bupranolol, (±)-nadolol, (±)-CGP12177A and (±)-carteolol belong to aryloxypropanolamine class (see Fig. 1 for chemical structure). The chemical structure of the above drugs closely resembles each other. However, the drugs exhibited a variety of functional responses at atypical β/β3-adrenoceptors. (±)-Bupranolol possesses antagonistic activities at atypical β-adrenoceptors Kaumann, 1989, Horinouchi and Koike, 1999a, Horinouchi and Koike, 1999b, whereas (±)-CGP12177A behaves as an agonist at atypical β-adrenoceptors in the guinea pig duodenum and gastric fundus Horinouchi and Koike, 1999a, Horinouchi and Koike, 1999b. Blin et al. (1993) showed that (±)-pindolol possessed agonistic properties with an intrinsic activity of 0.55 at β3-adrenoceptors in Chinese hamster ovary cells expressing the human β3-adrenoceptors. However, Hoey et al. (1996a) had reported that (±)-pindolol acts as an antagonist at β3-adrenoceptors in the rat ileum. Furthermore, (±)-carteolol possesses both agonistic and antagonistic activities at atypical β-adrenoceptors on the guinea pig duodenum (Horinouchi and Koike, 2000) and at β3-adrenoceptors on brown fat cells from mouse, rat and hamster (Zhao et al., 1998). Recently, the aryloxypropanolamines SB-226552 and its analogues, which resemble (±)-CGP12177A structurally, have been developed as the selective β3-adrenoceptor agonist for Chinese hamster ovary cells expressing the human β3-adrenoceptors (Sennitt et al., 1998). Thus, aryloxypropanolamine compounds show various activities at atypical β/β3-adrenoceptors. We therefore considered that the aryloxypropanolamine compounds possesses the agonistic activity at atypical β-adrenoceptors.
The objective of the present study is to further characterize atypical β-adrenoceptors in the guinea pig duodenum. Since recent studies suggested that atypical β-adrenoceptors could become a target for the development of new drugs in the treatment of obesity (Arch et al., 1984), gastrointestinal tract disorders Anthony, 1996, Bahl et al., 1996 and non-insulin-dependent diabetes (Yamamoto et al., 1997), the determination of stereochemical specificity for atypical β-adrenoceptors would be important to avert their side-effects of potential clinical relevance (Giudice et al., 1989). Therefore, we have used enantiomers of catecholamines (isoprenaline, noradrenaline and adrenaline) and aryloxypropanolamines (alprenolol and pindolol) in order to examine the stereochemical requirements of atypical β-adrenoceptors in the guinea pig duodenum. In addition, we have carried out the structure–activity relationship studies to clarify the chemical structure requirements of atypical β-adrenoceptors. Selective β2-adrenoceptor agonists ((±)-fenoterol, (±)-clenbuterol and (±)-salbutamol), which are similar to BRL37344, have been used to clarify whether the three drugs act with agonistic activity at atypical β-adrenoceptors. Moreover, in order to assess the agonistic effects of aryloxypropanolamines at atypical β-adrenoceptors, we have carried out functional experiments, which were established by Horinouchi and Koike (1999a) for atypical β-adrenoceptors in the guinea pig duodenum.
Section snippets
Animals and tissue preparation
Male Hartley guinea pigs weighing 300–500 g (Saitama Experimental Animals, Saitama, Japan) were used in accordance with the Guide for the Care and Use of Laboratory Animals of Toho University School of Pharmaceutical Sciences, and the protocol of the present study was approved by the Institutional Animal Care and Use Committee. Guinea pigs were housed under laboratory standard conditions on a 12-h light/dark cycle (lights on 8:00 AM; lights off 8:00 PM) in temperature- (20–22°C) and relative
Stereoselectivity
The stereoisomers of catecholamines (isoprenaline, noradrenaline and adrenaline) and aryloxypropanolamines (alprenolol and pindolol) induced concentration-dependent relaxations of the guinea pig duodenum (Fig. 2). The pD2 values and intrinsic activities of these drugs are summarized in Table 1. The (−)-enantiomers of isoprenaline and noradrenaline were more potent than its (+)-enantiomers (P<0.05), while the maximal relaxations induced by (−)-enantiomer and its (+)-enantiomer were not
Discussion
Pharmacological characteristics for atypical β/β3-adrenoceptors were described as follows: (i) high potency for a novel class of compounds, initially described as potent activators of lipolysis and thermogenesis in white and brown adipose tissues (e.g., BRL37344); (ii) partial agonist activities of several β1- or β2-adrenoceptor antagonists reflecting intrinsic sympathomimetic activities in heart tissue (e.g., CGP12177A); (iii) atypically low affinities and potencies for conventional
Acknowledgements
We thank Kaken Pharmaceutical (Tokyo, Japan) for generously providing (±)-bupranolol hydrochloride.
References (33)
- et al.
The human β3-adrenoceptor: the search for a physiological function
Trends Pharmacol. Sci.
(1994) - et al.
Inhibition of rat colonic motility and cardiovascular effects of new gut-specific beta-adrenergic phenylethanolaminotetralines
Life Sci.
(1989) - et al.
β-Adrenoceptor studies: III. On the beta-adrenoceptors in rat adipose tissue
Eur. J. Pharmacol.
(1974) - et al.
Characterization of atypical β-adrenoceptors in the guinea pig duodenum
Eur. J. Pharmacol.
(1999) - et al.
Partial agonist activity of carteolol on atypical β-adrenoceptors in the guinea pig duodenum
Eur. J. Pharmacol.
(2000) Is there a third heart β-adrenoceptor?
Trends Pharmacol. Sci.
(1989)- et al.
Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle
Eur. J. Pharmacol.
(1996) - et al.
Persistent β-adrenoceptor blockade with alkylating pindolol (BIM) in guinea-pig left atria ant trachea
Biochem. Pharmacol.
(1988) Chirality in α- and β-adrenoceptor agonists and antagonists
Tetrahedron
(1991)- et al.
Function and regulation of the β3-adrenoceptor
Trends Pharmacol. Sci.
(1996)
FR149175, a β3-adrenoceptor-selective agonist, is a possible therapeutic agent for non-insulin-dependent diabetes mellitus
Jpn. J. Pharmacol.
Is the adipocyte β-adrenoceptor a prototype for the recently cloned atypical ‘β3-adrenoceptor’?
Trends Pharmacol. Sci.
β3-Adrenoceptor agonists: future anti-inflammatory drugs for the gastrointestinal tract?
Aliment. Pharmacol. Ther.
β3- and atypical β-adrenoceptors
Med. Res. Rev.
Atypical β-adrenoceptor on brown adipocytes as target for anti-obesity drugs
Nature
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