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  • br Experimental procedures br Results br Discussion br Ackno


    Experimental procedures
    Introduction β-Adrenergic receptors (β-ARs) belong to the superfamily of membrane proteins termed G protein-coupled receptors. β-ARs are distributed in the effector β-Sitosterol of most of the sympathetic nerve fibers, and the receptors are of three types, the β1 receptor, the β2 receptor and the β3 receptor. In mouse models of breast and prostate carcinomas [1,2], as well as malignant melanoma and leukemia [3,4], β-ARs antagonists have been found to block stress-induced enhancement of tumor progression and/or metastasis without influencing primary tumor growth in vivo or tumor cell proliferation in vitro. β-ARs antagonists alone or in combination with nonsteroidal anti-inflammatory agents (NSAID) have also been found to inhibit surgery-induced metastasis in animal model [3,5,6]. Preclinical laboratory models and human pharmaco-epidemiologic studies both indicate that β-antagonists are likely to be the most effective drugs in inhibiting the micrometastatic spread of early-stage tumors [7]. It has been found that β3-AR plays a significant role in regulating lipolysis and thermogenesis in both rodent and human adipose tissue. In rodent white adipose tissue, β3-AR accounts for 90% of the β-ARs on the cell surface [8]. Data show that chronic inflammation together with β-adrenergic activation functionally cooperate in the pathogenesis of increased adipose tissue thermogenesis in cachexia [9]. β-adrenergic blockers can reduce white blood cell adipose tissue (WAT) browning, decrease the severity of cachexia. β3-AR blockade may protect against cachexia by means of decreased lipolysis [10]. A few antagonists of β3-AR have been identified. At present, there are two typical β3-AR inhibitors: aryloxy propanolamine tetrahydrate β3-AR inhibitor (SR59230A) [11] and aryloxypropanolamine β3-AR inhibitor (L-748,337), and their structures are shown in Fig. 1. SR59230A displays high affinity at human cloned β1-AR and β2-AR. Therefore, SR59230A is a potent and nonselective β-AR antagonist [12]. In contrast, L-748,337 displays more than 90-fold selectivity for human β3-AR over β1-AR, 45-fold selectivity for human β3-AR over β2-AR, respectively [12]. In this study, we clarified the process of exploring and developing potent and selective β3-AR antagonists. Meanwhile, we discussed the structure-relationship (SAR) data that deviated from that of the aryloxypropanolamine chemotype. Our design concept is outlined in Fig. 2. We planned to introduce 2-ethylphenyl group or 1H-indole group into the left-wing (part A) and to introduce urea group into the right-wing (part B) to attempt to improve β3-AR antagonist activity. We design compounds I based on an aryloxypropanolamine scaffold to facilitate rapid synthesis and SAR evaluation. This paper describes these efforts and the discovery of a novel, potent and selective human β3-AR antagonist. These compounds would maintain favorable activities in vitro and in vivo with decreasing the severity of cancer cachexia and inhibiting the growth of cancer cells.
    Results and discussion
    Conclusion In summary, a series of novel L-748,337 derivatives as selective human β3-AR antagonists were designed and synthesized to explore their biological activity and SAR with the lead compound, L-748,337. SAR analysis indicated that 1H-indole moiety derivatives showed higher β3-AR antagonist activity than that of 3-(acetamidomethyl)phenyl and 2-ethylphenyl moiety in part A, and the rank of order of potency seemed to be 1H-indole > 3-(acetamidomethyl)phenyl > 2-ethylphenyl. In the part B position, the connection moiety was crucial for the β3-AR antagonist activity, and the preferred group was ureido moiety. For the 1H-indole moiety antagonists of the human β3-AR described herein demonstrates in this receptor of binding interaction that can accommodate small (23d) to larger and bulkier substituents.