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Xinrong Tian,
Rajesh K Mishra,
Adrian G Switzer,
X Eric Hu,
Nick Kim,
Adam W Mazur,
Frank H Ebetino,
John A Wos,
Doreen Crossdoersen,
Beth B Pinney,
Julie A Farmer, Russell J Sheldon
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ABSTRACT: The design and synthesis of a series of potent 1,3,4-trisubstituted-2-oxopiperazine based MC4 agonists are described. The tripeptidomimetic analogs (12a,b and 23) and the dipeptidomimetic 27 displayed single-nanomolar binding affinity and agonist potency for MC4R and excellent selectivity for MC4R relative to MC1R.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(17):4668-73. · 2.55 Impact Factor
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Xinrong Tian,
Timothy B Field,
Adrian G Switzer,
Adam W Mazur,
Frank H Ebetino,
John A Wos,
Steve M Berberich,
Lalith R Jayasinghe,
Cindy M Obringer,
Martin E Dowty,
Beth B Pinney,
Julie A Farmer,
Doreen Crossdoersen, Russell J Sheldon
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ABSTRACT: The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the 2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine diastereomers investigated, analogues with the (2S,4R) configuration were the most potent agonists across the three receptors, followed by those possessing the (2S,4S) configuration.
Journal of Medicinal Chemistry 08/2006; 49(15):4745-61. · 5.25 Impact Factor
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Xinrong Tian,
Xuemei Chen,
Lixian Gan,
Jeffery C Hayes,
Adrian G Switzer,
Mark G Solinsky,
Frank H Ebetino,
John A Wos,
Beth B Pinney,
Julie A Farmer,
Doreen Crossdoersen, Russell J Sheldon
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ABSTRACT: The first synthesis of Tic-D-Phe Psi[CH(2)-CH(2)] isostere is described, which features diastereoselective alkylation of the tricyclic lactam 14. The use of this novel dipeptide isostere in the development of melanocortin agonists has been demonstrated by the synthesis of peptidomimetic 7 and non-peptidic ligand 27. Both compounds displayed significant binding and agonist potency at the MC4R.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(6):1721-5. · 2.55 Impact Factor
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ABSTRACT: A wide range of experimental evidence implicates a critical role for melanocortin signaling in the control of food intake and body adiposity. Melanocortin receptor agonists such as MT-II potently reduce food intake and body weight, making such agonists potential therapeutics for obesity. The critical concept addressed by the present experiments is whether the homeostatic effects of melanocortin agonists directly regulate food intake or whether the effects on food intake are secondary, with the primary effects being the regulation of body weight and adiposity. To investigate this, we compared the effect of various doses of MT-II given via osmotic minipump for 28 d to alter food intake, body weight, and body fat in dietary-induced obese rats. In addition, before the implantation of the minipump, dietary-induced obese rats were weight reduced by differing amounts using varying levels of food restriction. The results show that in food-restricted rats, MT-II-treated rats consume significantly more calories than those receiving MT-II after ad libitum access to food. More importantly, regardless of the widely differing levels of body fat among the different dietary treatments employed, body fat at the end of the study was determined exclusively by the dose of MT-II, with MT-II-treated rats having less body fat than vehicle-treated rats. These experiments support the hypothesis that melanocortin signaling primarily regulates total body adiposity and that food intake is adjusted as necessary to achieve a specific level of body adiposity.
Endocrinology 10/2005; 146(9):3732-8. · 4.46 Impact Factor
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ABSTRACT: A series of proline based melanocortin ligands has been developed on the basis of initial piperazine leads by using a more conformationally rigid scaffold. A number of these novel ligands showed significant binding affinity for MC3 and MC4 receptors.
Bioorganic & Medicinal Chemistry Letters 07/2005; 15(11):2819-23. · 2.55 Impact Factor
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ABSTRACT: Of the two known vasoactive intestinal peptide receptors (VPAC1R and VPAC2R), the VPAC2R is expressed in skeletal muscle. To evaluate the function of the VPAC2R in the physiological control of skeletal muscle mass, we utilized the VPAC1R selective agonist [K15,R16,L27]VIP(1-7) GRF(8-27)-NH2 and the VPAC2R selective agonist Ro-25-1553 to treat mice and rats undergoing either nerve damage-, corticosteroid-, or disuse-induced skeletal muscle atrophy. These analyses demonstrated that activation of VPAC2R, but not VPAC1R, reduced the loss of skeletal muscle mass and force during conditions of skeletal muscle atrophy resulting from corticosteroid administration, denervation, casting-induced disuse, increased skeletal muscle mass, and force of nonatrophying muscles. These studies indicate that VPAC2R agonists may have utility for the treatment of skeletal muscle-wasting diseases.
Journal of Applied Physiology 03/2005; 98(2):655-62. · 3.75 Impact Factor
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Richard T Hinkle,
Elizabeth Donnelly,
David B Cody,
Steven Samuelsson,
Jana S Lange,
Mary Beth Bauer,
Mark Tarnopolsky, Russell J Sheldon,
Sarah C Coste,
Eric Tobar,
Mary P Stenzel-Poore,
Robert J Isfort
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ABSTRACT: Two receptors activated by the corticotropin-releasing factor (CRF) family of peptides have been identified, the CRF 1 receptor (CRF1R) and the CRF 2 receptor (CRF2R). Of these, the CRF2R is expressed in skeletal muscle. To understand the role of the CRF2R in skeletal muscle, we utilized CRFR knockout mice and CRF2R-selective agonists to modulate nerve damage and corticosteroid- and disuse-induced skeletal muscle atrophy in mice. These analyses demonstrated that activation of the CRF2R decreased nerve damage and corticosteroid- and disuse-induced skeletal muscle mass and function loss. In addition, selective activation of the CRF2R increased nonatrophy skeletal muscle mass. Thus we describe for the first time a novel activity of the CRF2R, modulation of skeletal muscle mass.
AJP Endocrinology and Metabolism 11/2003; 285(4):E889-98. · 4.75 Impact Factor
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Stephen C Benoit,
Ellen L Air,
Kihmberly Wilmer,
Patrick Messerschmidt,
Karen M B Hodge,
Melissa B Jones,
Dawn M M Eckstein,
Charles C McOsker,
Randy J Seeley,
Stephen C Woods, Russell J Sheldon
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ABSTRACT: The conditioned taste aversion (CTA) is routinely used to assess the aversive consequences of anorexic agents, including potential pharmacological therapies for obesity. In a typical CTA paradigm, rats briefly sampling a novel tastant (e.g., saccharin) are acutely administered with toxin (e.g., lithium chloride, LiCl). After as few as one taste-toxin pairing, rats will reliably avoid the novel tastant. This paradigm is frequently used for the assessment of possible aversive consequences of drugs that are candidates for pharmacological therapies. The degree to which the drug supports development of a CTA is interpreted as an index of its aversive properties. Difficulties with previous work include the inability to assess affects on food intake and CTA simultaneously, particularly during chronic drug administration. We report here two novel CTA paradigms for the assessment of appetitive and aversive consequences of anorexic agents, simultaneously. In the first experiment, animals receive an intraoral infusion of a novel and highly palatable tastant immediately prior to administration of increasing doses of LiCl. In the second experiment, rats were implanted intraperitoneally with osmotic minipumps that chronically delivered a low dose of LiCl for 7 days. LiCl did not affect short or long term food intake in either experiment. However, LiCl did support the development of a CTA in both paradigms. These results suggest that both the appetitive and aversive consequences of anorexic agents can be assessed simultaneously during either acute or chronic drug administration.
Physiology & Behavior 10/2003; 79(4-5):761-6. · 2.87 Impact Factor
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ABSTRACT: Analyses were performed to evaluate the roles of the beta1- and beta2-adrenergic receptors in the skeletal muscle hypertrophy and anti-atrophy response to the beta-adrenergic agonist, clenbuterol. Treatment of wild-type mice with clenbuterol resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. Treatment of beta1-adrenergic receptor knockout mice with clenbuterol also resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. In contrast, in beta2-adrenergic receptor knockout mice and in mice lacking both the beta1- and beta2-adrenergic receptors, clenbuterol treatment did not result in hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles, nor did it inhibit denervation-induced atrophy in these muscles. Together these data demonstrate that the beta2-adrenergic receptor is responsible for both the skeletal muscle hypertrophy and anti-atrophy effects of the beta-adrenergic agonist clenbuterol.
Muscle & Nerve 06/2002; 25(5):729-34. · 2.37 Impact Factor
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ABSTRACT: We show that magnetic resonance imaging (MRI) can be used to quantify the amount of muscle in the lower legs of adult rats and to noninvasively monitor the onset and progression of denervation-induced atrophy. Muscle cross-sectional areas determined from 2D gradient-echo MR images allow longitudinal quantification of the protective effects of a β2-adrenergic agonist clenbuterol. We also show that the estimation of clenbuterol's efficacy is improved by computation of the muscle volume. Rapid animal throughput and the ability to accurately estimate efficacy make MRI an attractive technology for studying skeletal muscle atrophy and hypertrophy, allowing the evaluation of potential therapies in longitudinal studies. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1647–1658, 2001
Muscle & Nerve 11/2001; 24(12):1647 - 1658. · 2.37 Impact Factor
