作者: Liu, Wen ; Gay, Elaine A. ; Liu, Jiaqi ; Jin, Chunyang ; Besheer, Joyce ; Guan, Dongliang ; Lin, Sophia ; Lovelock, Dennis F. ; Van Voorhies, Kalynn J.

AbstractThere is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising target for therapeutic intervention is the relaxin family peptide 3 (RXFP3) receptor, a cognate receptor for neuropeptide relaxin‐3, which has previously been implicated in regulating alcohol drinking behavior. Recently, we developed the first small‐molecule RXFP3‐selective negative allosteric modulator (NAM) RLX‐33. Therefore, the goal of the present work was to characterize the impact of this novel NAM on affective‐related behaviors and alcohol self‐administration in rats. First, the effects of RLX‐33 were tested on alcohol and sucrose self‐administration in Wistar and alcohol‐preferring P rats to determine the dose–response profile and specificity for alcohol. Then, we assessed the effects of systemic RLX‐33 injection in Wistar rats in a battery of behavioral assays (open‐field test, elevated zero maze, acoustic startle response test, and prepulse inhibition) and tested for alcohol clearance. We found that the lowest effective dose (5 mg/kg) reduced alcohol self‐administration in both male and female Wistar rats, while in alcohol‐preferring P rats, this effect was restricted to males, and there were no effects on sucrose self‐administration or general locomotor activity. The characterization of affective and metabolic effects in Wistar rats generally found few locomotor, affective, or alcohol clearance changes, particularly at the 5 mg/kg dose. Overall, these findings are promising and suggest that RXFP3 NAM has potential as a pharmacological target for treating AUD.

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2022-06-09·Journal of Medicinal Chemistry1区 · 医学

Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System

1区 · 医学

Article

作者: Besheer, Joyce ; Jin, Chunyang ; Van Voorhies, Kalynn ; Gay, Elaine A. ; Mathews, Kelly M. ; Guan, Dongliang ; Vasukuttan, Vineetha

The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 (33) that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.

2008-07-01·Osteoporosis International2区 · 医学

Effects of teriparatide on serum calcium in postmenopausal women with osteoporosis previously treated with raloxifene or alendronate

2区 · 医学

Article

作者: F. Cosman ; E. V. Glass ; L. Xie ; C. P. Recknor ; R. A. Wermers ; J. H. Krege

The effect of teriparatide (20 microg/day) on serum calcium was examined in postmenopausal women previously treated with alendronate or raloxifene. Women previously treated with alendronate or raloxifene who added teriparatide or switched to teriparatide did not have clinically meaningful increases in mean predose serum calcium.INTRODUCTIONThe effects of a 6-month treatment with teriparatide (20 microg/day; rhPTH(1-34), TPTD) on serum calcium (Ca) was examined in a prospective study of postmenopausal women previously treated with alendronate (70 mg/week or 10 mg/day [ALN] or raloxifene 60 mg/d [RLX]) for > or =18 months.METHODSWomen continued their usual ALN or RLX during a 2-month antiresorptive phase. Women previously treated with ALN were randomized to add TPTD (n = 52) or switch to TPTD (n = 50) and women previously treated with RLX were randomized to add TPTD (n = 47) or switch to TPTD (n = 49). All were to take at least 500 mg/day of elemental Ca and 400-800 IU/day of vitamin D.RESULTSPredose mean serum Ca did not significantly change in groups adding TPTD to either RLX or ALN treatment. In patients who switched from RLX or ALN to TPTD, mean serum Ca increased by 0.05 mmol/L and 0.04 mmol/L respectively. Only 1 patient had the predefined calcium endpoint of serum calcium > 2.76 mmol/L (11 mg/dL) at more than one visit.CONCLUSIONSWomen previously treated with ALN or RLX who added TPTD or switched to TPTD did not have clinically meaningful increases in mean predose serum Ca.

100 项与 RLX-33 相关的药物交易

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