The Therapeutic Potential of 2-{[4-(2-methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles as Ligands for Alpha1-Adrenergic Receptor - Comparative In Silico and In Vitro Study

• Published in: Applied biochemistry and biotechnology Vol. 194; no. 8; pp. 3749 - 3764
• Main Authors: Penjišević, Jelena Z., Šukalović, Vladimir B., Andrić, Deana B., Suručić, Relja, Kostić-Rajačić, Sladjana V.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2022; Springer Nature B.V
• Subjects: absorption; Adrenergic receptors; Anaphylaxis; Angina; Angina pectoris; Animal models; animals; Antifungal agents; Asthma; Biochemistry; Biotechnology; Chemistry; Chemistry and Materials Science; Comparative analysis; computer simulation; Congestive heart failure; excretion; G protein-coupled receptors; heart failure; Hyperplasia; Hypertension; Hyperthyroidism; Hypertrophy; Imidazole; imidazoles; Lead compounds; ligands; Molecular docking; Molecular dynamics; Original Article; Pharmacokinetics; Prostate; Receptors (physiology); therapeutics; Binding assay; Molecular dynamics simulations; Pharmacokinetics; Alpha1-adrenergic receptors; Docking analyses; Arylpiperazines
• ISSN: 0273-2289; 1559-0291
• DOI: 10.1007/s12010-022-03922-8

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl]alkyl}-1 H -benzo[ d ]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds ( 2 – 5 , 8 , and 12 ) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.