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Synthesis and in vitro and in vivo characterization of highly ?1-selective ?-adrenoceptor partial agonists.

ABSTRACT: ?-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human ?-adrenoceptor subtype involved in these diseases, yet few truly ?1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1), (1) a selective ?1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1's aromatic nitrile afforded 19, a ligand with similar ?1-adrenoceptor selectivity and partial agonism (log KD of -7.75 and -5.15 as an antagonist of functional ?1- and ?2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (?1)). In vitro ?-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and ?1-selectivity.

SUBMITTER: Mistry SN

PROVIDER: S-EPMC3694353 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Synthesis and in vitro and in vivo characterization of highly β1-selective β-adrenoceptor partial agonists.

Mistry Shailesh N SN Baker Jillian G JG Fischer Peter M PM Hill Stephen J SJ Gardiner Sheila M SM Kellam Barrie B

Journal of medicinal chemistry 20130510 10

β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1), (1) a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1's aromatic nitrile afforded 19, a ligand with ...[more]

PMID: 23614528

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Project description:The adipose-derived hormone, adiponectin (ApN), has a role in fuel homoeostasis, insulin action and atherosclerosis. Regulation of ApN by catecholamines has scarcely been investigated. We examined the effects of beta-adrenergic agonists (and their second messenger, cAMP) on ApN gene expression, production and secretion in mouse in vitro and in vivo; their effects in human fat were also briefly studied in vitro. beta-Adrenergic agonists and cAMP inhibited ApN gene expression in human visceral adipose tissue. Likewise, cAMP down-regulated ApN mRNAs in cultured mouse explants from visceral and subcutaneous regions. The amount of ApN released into the medium decreased concomitantly. cAMP also caused qualitative changes in ApN secretion. Under basal conditions, ApN was secreted as a single 32 kDa species. In the presence of cAMP, an additional and probably immature (not modified post-translationally) 30 kDa species was also sorted. This altered secretion resulted from cAMP-induced quantitative and qualitative changes of ApN within the adipocyte. Under basal conditions, the 32 kDa form of ApN was mainly associated with high-density microsomes (HDMs), while the 30 kDa species was confined to a pool recovered with the cytosol fraction. cAMP depleted intracellular ApN at the expense of both HDM and cytosol fractions, and abnormally targeted ApN species to the different subcellular compartments as a result of impaired maturation. beta-Adrenergic agonists mimicked the inhibitory effects of cAMP on ApN mRNA and secretion, the beta(3)-agonist BRL37344 being the most potent. Administration of BRL37344 to mice reduced ApN mRNAs in both adipose regions, and ApN levels in plasma. In conclusion, beta-agonists inhibited ApN production and maturation, and thus exerted a dual (pre- and post-translational) negative effect on ApN secretion by cultured mouse adipose explants. ApN inhibition by beta-agonists was reproduced in mouse in vivo and in humans in vitro. ApN down-regulation may have an important role in fuel homoeostasis, insulin resistance and stress-induced atherosclerosis.

Dataset Information

Synthesis and in vitro and in vivo characterization of highly ?1-selective ?-adrenoceptor partial agonists.

Publications

Synthesis and in vitro and in vivo characterization of highly β1-selective β-adrenoceptor partial agonists.

Similar Datasets

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