Promising anticonvulsant and/or analgesic compounds among 5‐chloro‐2‐ or 5‐chloro‐4‐methyl derivatives of xanthone coupled to aminoalkanol moieties—Design, synthesis and pharmacological evaluation

A series of 10 aminoalkanol derivatives of 5‐chloro‐2‐ or 5‐chloro‐4‐methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity a...

Full description

Saved in:

Bibliographic Details
Published in:	Chemical biology & drug design Vol. 101; no. 2; pp. 278 - 325
Main Authors:	Mazur, Gabriela, Pańczyk‐Straszak, Katarzyna, Rapacz, Anna, Kiszela, Jan, Smolik, Magdalena, Gawlik, Maciej, Walczak, Maria, Czekajewska, Joanna, Poloczek, Celina, Karczewska, Elżbieta, Żesławska, Ewa, Nitek, Wojciech, Niedbał, Anna, Leśniak, Joanna, Ciapala, Katarzyna, Pawlik, Katarzyna, Mika, Joanna, Waszkielewicz, Anna M.
Format:	Journal Article
Language:	English
Published:	England 01-02-2023
Subjects:	aminoalkanol analgesic activity Animals anticonvulsant activity Anticonvulsants - pharmacology Anticonvulsants - therapeutic use Electroshock Mice Seizures - drug therapy sigma‐1 receptor sigma‐2 receptor Structure-Activity Relationship xanthone Xanthones - chemistry Xanthones - pharmacology Xanthones - therapeutic use sigma-2 receptor analgesic activity sigma-1 receptor anticonvulsant activity aminoalkanol xanthone
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	A series of 10 aminoalkanol derivatives of 5‐chloro‐2‐ or 5‐chloro‐4‐methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity and protective index value were obtained for 3: 5‐chloro‐2‐([4‐hydroxypiperidin‐1‐yl]methyl)‐9H‐xanthen‐9‐one hydrochloride. Compounds: 1–3, 7 and 10 revealed ED50 values in MES test: 42.78, 31.64, 25.76, 46.19 and 52.50 mg/kg b.w., respectively. 3 showed 70% and 72% of inhibition control specific binding of sigma‐1 (σ1) and sigma‐2 (σ2) receptor, respectively. 3 exhibited also antinociceptive activity at dose 2 mg/kg b.w. after chronic constriction injury in mice. 1, 3, 7 and 10 were evaluated on gastrointestinal flora and proved safe. In genotoxicity test (UMU‐Chromotest) compounds 1, 7 and 10 proved safe at dose 150–300 μg/ml. The pharmacokinetic analysis showed rapid absorption of all studied molecules from the digestive tract (tmax = 5–30 min). The bioavailability of the compounds ranged from 6.6% (1) to 16% (10). All studied compounds penetrate the blood–brain barrier with brain to plasma ratios varied from 4.15 (3) to 7.6 (compound 7), after i.v. administration, and from 1 (7) to 5.72 (3) after i.g. administration. A series of xanthone derivatives has been synthesized and screened for anticonvulsant and/or analgesic in neuropathic pain activity (mice, i.p.). For compound 3: MES ED50 = 25.76, antinociceptive activity at 2 mg/kg (chronic constriction injury), inhibition of control specific binding for sigma‐1 = 70% and for sigma‐2 = 72%.
ISSN:	1747-0277 1747-0285
DOI:	10.1111/cbdd.14102