Medetomidine Analogs as α₂-Adrenergic Ligands. 2. Design, Synthesis, and Biological Activity of Conformationally Restricted Naphthalene Derivatives of Medetomidine

Abstract

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

“…The preparation of different conformationally restricted analogs has allowed it to be shown that the flexibility of the bridge plays a key role in the fulfillment of the biological profile. In fact, while potency and selectivity of the naphthyl-derivative 81 at α 2 -ARs vs. α 1 -ARs are similar to those of medetomidine (K i α 1 /K i α 2 = 44.4) [163], the α 2 -selectivity is instead markedly decreased in the perinaphthanyl-(82), phenanthrenyl-(83), tetralin- (84), and indano-derivatives (85) [117].…”

Medetomidine Analogs as α2-Adrenergic Ligands. 3. Synthesis and Biological Evaluation of a New Series of Medetomidine Analogs and Their Potential Binding Interactions with α2-Adrenoceptors Involving a “Methyl Pocket”

“…Medetomidine ( 1 ) is the prototype of a class of α-adrenoceptor agents . We previously described the synthesis, biological evaluation, and computer modeling studies of the 4-substituted imidazoles as α-adrenoceptor agents. , Naphthyl analog 2a exhibited equal potency and higher selectivity at α 2 -adrenoceptors than medetomidine. Conformationally restricted analog 3a of the naphthyl series retained high binding affinity but low selectivity at α 2 -adrenoceptors.…”

“…During the course of our synthetic research, we conducted molecular modeling studies on the medetomidine-like analogs and found a common binding mode of the phenethylamines and the imidazoles with α 2 -adrenoceptors by superimposition of the imidazole analogs with (−)-α-methylnorepinephrine (α-MeNE) …”

Ligand- and Structure-Based Analysis of Deep Learning-Generated Potential α2a Adrenoceptor Agonists

“…For our purposes, activation capability was defined as the experimental evidence of α 2A -AR agonism via either functional assay or an agonist response-like binding profile. After converting all structures to the RDKit () canonical simplified molecular-input line-entry system (SMILES) form and deduplicating, a set of 206 agonists was ultimately compiled from 39 sources. − A set of 2043 decoys was generated using the Database of Useful Decoys: Enhanced (DUD-E) and added to the library. For use as an external test set, the α 2A -AR agonist and decoy dataset from the GPCR Ligand Library/GPCR Decoy Database (GLL/GDD) was downloaded.…”