The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V1A receptor antagonists

Napier, Susan; Wishart, Grant; Arbuckle, William; Baker, James Α.; Barn, David R.; Bingham, Matilda; Brown, Angus R.; Byford, Alan; Claxton, Chris; Craighead, Mark; Buchanan, Kirsteen; Fielding, Lee A.; Gibson, Lindsay; Goodwin, Richard; Goutcher, Susan; Irving, Nicholas; MacSweeney, Cliona; Milne, Rachel; Mort, Chris; Presland, Jeremy; Sloan, Hazel; Thomson, Fiona; Turnbull, Z.; Young, Trevor

doi:10.1016/j.bmcl.2011.02.096

Cited by 6 publications

(2 citation statements)

References 8 publications

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“…[29,30] The azabicyclo[3.2.1]octane moiety composes the core structure of various biologically active compounds with antiproliferative, antimicrobial, analgesic, and antiinflammatory effects that are occasionally exploited as drugs. [31][32][33][34][35][36] In 1909, cocaine (COC) (Figure 1a), a natural product containing azabicyclo[3.2.1]octane that is extracted from the leaves of the coca bush (Erythroxylum coca) plant, [37] was reported as an anticancer drug by Gilchrist. [38] Research in this regard has led to the recent development of different binary [39,40] and heteroleptic [41] metal complexes of COC exhibiting anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structural characterization, density functional theory calculations, and antimicrobial, anticancer, and antimetastatic properties of nanosized heteroleptic complexes of cocaine/TMEDA with d‐block metal ions

Abdallah

Zaki

Mahmoud

et al. 2021

Applied Organom Chemis

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In the field of transition metal chemistry, the development of transition metal‐based drugs for the treatment of diseases such as cancer or microbial infections with minimization of adverse effects and drug resistance constitutes an active area of research. Herein, eight novel nanosized heteroleptic complexes of cocaine/TMEDA with the formula [M(COC)(TMEDA)Cly(OH2)z]nCl·xH2O (M = Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II); COC = cocaine; TMEDA = N,N,N′,N′‐tetramethylethylenediamine, y = 1–2; z = 0–1; n = 0–1; and x = 0–2) were synthesized and structurally characterized via elemental analysis, molar conductivity, mass spectrometry, and spectroscopic and microscopic techniques. The thermal properties and kinetic thermodynamic parameters of the synthesized complexes were also studied. The geometry and electronic structures were investigated via density functional theory (DFT) calculations. The antiproliferative activity of the complexes on HepG‐2 and MCF‐7 cancer cell lines was quantified via MTT assay. The Fe(III) and Cd(II) complexes exhibited promising cytotoxic activities against the HepG‐2 and MCF‐7 cancer cell lines, respectively, with minimum effect on HFB4 human normal cells. Further molecular mechanistic studies were performed on the Cd(II) complex to inspect its influence on different cancer pathophysiology‐related processes in the MCF‐7 cell line including metastasis, apoptosis, and cellular oxidative stress and on the cellular levels of the human tumor suppressor nuclear proteins p21 and p27. The results revealed that the Cd(II) complex is a promising anticancer agent that acts through several molecular mechanisms with minimum effect on the normal cells and with additional antimetastatic properties. Furthermore, the antibacterial and antifungal activities of the prepared complexes were investigated.

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Section: Introductionmentioning

confidence: 99%

Synthesis, structural characterization, density functional theory calculations, and antimicrobial, anticancer, and antimetastatic properties of nanosized heteroleptic complexes of cocaine/TMEDA with d‐block metal ions

Abdallah

Zaki

Mahmoud

et al. 2021

Applied Organom Chemis

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“…At a preclinical stage, Johnson and Johnson demonstrated the in vivo efficacy of 5 (JNJ-17308616) in a rat model of anxiety . More recently, MSD disclosed a novel series of CNS penetrant V1a antagonists exemplified by 6 with a good affinity for the rat receptor . Peripheral in vivo functional V1a antagonism was demonstrated by the reversal of V1a mediated arginine vasopressin (AVP) induced blood pressure increases in conscious rats.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Highly Selective Brain-Penetrant Vasopressin 1a Antagonists for the Potential Treatment of Autism via a Chemogenomic and Scaffold Hopping Approach

et al. 2015

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From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

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Structural characterization, thermal, DFT, cytotoxicity, and antimetastatic properties of cocaine complexes with La(III), Er(III), and Yb(III)

et al. 2020

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The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V1A receptor antagonists

Cited by 6 publications

References 8 publications

Synthesis, structural characterization, density functional theory calculations, and antimicrobial, anticancer, and antimetastatic properties of nanosized heteroleptic complexes of cocaine/TMEDA with d‐block metal ions

Synthesis, structural characterization, density functional theory calculations, and antimicrobial, anticancer, and antimetastatic properties of nanosized heteroleptic complexes of cocaine/TMEDA with d‐block metal ions

Discovery of Highly Selective Brain-Penetrant Vasopressin 1a Antagonists for the Potential Treatment of Autism via a Chemogenomic and Scaffold Hopping Approach

Structural characterization, thermal, DFT, cytotoxicity, and antimetastatic properties of cocaine complexes with La(III), Er(III), and Yb(III)

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