Imidazoline Binding Sites (IBS) Profile Modulation:  Key Role of the Bridge in Determining I₁-IBS or I₂-IBS Selectivity within a Series of 2-Phenoxymethylimidazoline Analogues

Abstract

The alpha- and beta-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I(1)- and I(2)-IBS selectivity. The alpha-methylation appeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes (I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(-)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the -methylation tended toward I2-IBS selectivity (I2/I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I2/I1 = 1479) proved to be considerably more potent and selective with respect to I2-IBS subtypes.

Antagonism/Agonism Modulation to Build Novel Antihypertensives Selectively Triggering I1-Imidazoline Receptor Activation

“…In both cases, the presence of the methyl group in the bridge strongly disadvantaged the I 2 -IBS interaction. 13 Such observations suggested the existence of a "methyl pocket" in the α 2 -AR 17 and I 1 -IR, but not in the I 2 -IBS binding cavity. Compound 1 behaved as an antagonist at the three α 2 -AR subtypes.…”

“…Indeed, in in vivo studies, 3 displayed no cardiovascular effect and prevented the hypotensive and bradycardic action of clonidine. 13 The fact that several classes of substances, including those bearing an imidazoline ring, interact with α 2 -ARs and I 1 -IRs suggests that such systems might present analogies in the nature of some critical binding sites. 20 Based on this hypothesis, to modulate the biological profile of 3 from antagonism to agonism, recently, we prepared and studied its ortho phenyl derivative 4.…”

“…The absolute configuration S was assigned to the dextrorotatory enantiomer (+)-8 through X-ray diffraction analysis of its dibenzoyl-D-tartrate salt ( Figure 1). I 1 -IR affinity values for 5−9, obtained following previously described procedures, 13 are reported in Table 1 along with those of 3, 4, and their enantiomers, which were included for useful comparison. The data suggest that in the case of aromatic substituents, only a strong aromaticity, as that associated with the phenyl of 4 (pK i = 6.81) or the thiophenyl of 5 (pK i = 7.20) moieties, is favorable.…”

Stereochemical Sensitivity of the Human UDP-glucuronosyltransferases 2B7 and 2B17

“…Eudismic analysis (EA), in general, provides a valuable approach to elucidate the interaction between chiral compounds and their target proteins. 25,26 In addition, this analytical method is used in drug design and development to increase the selectivity and potency of chiral lead compounds toward their receptors. 27 In this study, the tools of EA were employed to identify the factors determining affinity and GlcA-transfer to edge closer to the mechanism of the UGT-catalyzed glucuronidation reaction at the molecular level.…”

Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction

“…17−19 At low dose 1 also reduced hyperanxiety-like behavior after alcohol intoxication. 20 In contrast, the −CHCH− bridge induced efficacious I 1 -and I 2 -IBS recognition, as demonstrated by tracizoline (3) (pK i : I 1 -IBS 7.72, I 2 -IBS 8.72, α 2 -ARs < 6), 21 whereas the −NH− CH 2 − chain might be tolerated by ligands addressed to I 1 -, I 2 -IBS and α 2 -ARs, as reported for 4 (pK i : I 1 -IBS 9.30, I 2 -IBS 7.48, α 2 -ARs 7.14). 22,23 Our studies also indicated that the introduction of suitable decorations in the ortho position of the phenyl ring conferred to the ligand an interesting profile modulation from antagonism to agonism.…”