Synthesis and Pharmacological Activity of New Carbonyl Derivatives of 1‐Aryl‐2‐iminoimidazolidine. Part 3. Synthesis and Pharmacological Activity of 1‐Aryl‐5,6(1H)dioxo‐2,3‐dihydroimidazo[1,2‐a]imidazoles.

Abstract

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Synthesis, central nervous system activity and structure–activity relationship of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization

“…We have previously reported a few series of 1-aryl-4,5-dihydro-1H-imidazol-2-amines derivatives which do not possess a protonable nitrogen atom but exhibit serotoninergic and antinociceptive activity mediated 2,[8][9][10][11] or not 12 through the opioid system. Encouraged by these results, we designed, synthesized and studied further four series of compounds (3a-3e, 4a-4e, 5a-5e, 6a-6e) (Scheme 1) [17][18][19][20] .…”

“…Consequently, non-classical pharmacophore models explaining opioid receptor activity were proposed as presented in Figure 2. These models involve a base (B), a hydrophobic (H) and aromatic moiety (Ar) or hydrogen bond acceptor (HA), hydrophobic (H), and aromatic groups (Ar) 5,[8][9][10][11] . Following the non-classical pharmacophore models for opioid receptor activity, we have previously reported several series of compounds with antinociceptive activity mediated through the opioid system (series A-E [8][9][10][11] ), partially mediated through opioid system (series F 2 ) or with a different mechanism of antinociceptive activity (series G 12 ), Figure 3.…”

Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

“…These incudes BMS986121, BMS986122 [12], as well as MS1 [13] and several of its analogs were identified mainly through large library screening. We have made an effort to develop novel antinociceptive compounds with confirmed [14][15][16] or probable [17][18][19][20][21] activity through MOR. All these compounds fulfill non-classical MOR opioid receptor pharmacophore model [15], further extended by our group [21] which involves a base, a hydrophobic and aromatic moiety or hydrogen bond acceptor, hydrophobic and aromatic groups.…”

“…Selected compounds from all the series exhibit antinociceptive properties in vivo reversed by naloxone which suggests that their antinociceptive activity is mediated by MOR. In addition, for selected compounds from the compound series described in references [14][15][16] EC 50 values to MOR were determined. In particular, we found that two previously reported compounds, 1 [21] and 2 [16] (Figure 1) probably are MOR PAMs.…”

New Drugs - From Necessity to Delivery

“…The most significant is that scientists have stopped looking at medicine as an anonymous collection of atoms, and started seeing it as a steric (shape of particles) with Current Issues in Pharmacy and Medical Sciences electrostatic interactions, of hydrophilic and hydrophobic activity -in other words, a substance with directional interactions in three-dimensional space. Therefore, it is important that while random synthesis are still continued to be performed, the testing of the resulting substances is more accurate and has been extended by new methods of analysis [8].…”