Design, Synthesis And Bioactivity Of Novel 3-Arylazepanes For μ And δ Opioid Receptors

Opioids are the most commonly prescribed analgesics to relieve moderate-to-severe pain. However, their clinical utilities are always limited by the serious side effects, such as respiratory depression and abuse potential. There has been increasing evidence that theδreceptor is involved in formation ofμ-mediated side effects, and opioids targeting onδreceptor may minimized these effects. So the compounds with mixedμ/δprofile are extremely valuable candidates for ideal analgesics without abuse potential. Meptazinol which belongs to 3-arylazepanes is a marketed analgesic drug with low addiction liability and respiratory depression. Bio-assays has revealed that (+)-meptazinol (1a) is aμand 8 mixed agonist, which may have a synergistic effect on its analgesic activities. And this is the start point of our research to explore novel opioids with mixedμ/δactivities, combined with the "message-address" concept and computer aided drug design.In the second section, 43 4-phenylpiperidines which have similar structures with 1a were employed in a 2D-QSAR study by neural network method. A four-point pharmacophore model has been suggested: besides two conservative components of electronegative nitrogen and phenyl, the addition of a lipophilic group on the nitrogen and a hydrogen-bonding donor group on the piperidine tend to significantly enhance their analgesic activities. This result implies that the introduction of similar groups on la may improve their activities onμorδreceptors.In the third section, based on the lipophilic pharmacophore proposed in the QSAR study, a series of N-phenylalkyl substituted derivatives were designed. Starting from 1a, the new compounds were prepared by N-demethylation and N-alkylation. The biological activity studies show that the N-benzyl substituted compound 5 is a potentμandδagonist, with 20 and 300 more fold than la, respectively. The N-phenethyl substituted compound 6a turns out to be an unexpectedδselective agonist, which is stronger then the well-knownδselective agonist SNC80. Interestingly, 6b, the enantiomer of 6a, is aμselective agonist activity and more potent than morphine. The discovery of these compounds is very instructive for the study of ligand-receptor interactions. 5 and 6a could be developed as clinical candidates.In the fourth section, a hydroxy group enlightened by the QSAR study was introduced to the 4 position of meptazinol. The synthesis was started from a known intermediate, followed by two-step reduction, optical resolution and O-demethylation. The absolute configuration, dominant conformation and e.e. value were also determined. The biological activity studies show that the introduction of hydroxy group does not enhance their activities on all three receptors, but the flexible azepane ring was found been constrained after this modification. It provides a useful tool for the further SAR studies. In the fifth section, in order to exert synergistic or conformation constrain effect, three compounds were designed using combination principles based on the results in third and fourth sections. It was found the new compound 22 (3R,4R) is an extremely potentμagonist (12pM), almost equivalent to the most potentμagonist ohmefentanyl. In addition, the constrained compound 23b (3R,4S) and 23c (3R,4R) turn out to be aμselective agonist andμ/δmixed agonist, which conforms the 3-aryl axial conformation is the bio-active conformation of 6a. 22, 23b and 23c could be developed as promising candidates for pain management. The study from third to fifth section indicates that the N-substitution in 3-arylazepanes may play an important role in their efficacy and receptor selectivity, which suggests a new address componentis on opioid receptors.In the sixth section, according to the classic pharmacophores of 8 selective ligands, various lipophilic groups as potentialδ"address" component were introduced on the 4 position of meptazinol. The synthesis was started from cis-16, trans-16, or 16c, followed by alcylation and O-demethylation. The biological activity study suggests the compound 44 (3R,4R) with a phenylacetate substitution is aμandδagonist, which is 15 and 6 more fold than la and itsμagonist activity is stronger than morphine. This result provides a second structural component which is responsible for the efficacy and receptor selectivity of 3-arylazepanes.In the seventh section, the conformations of the 3-aryl-4-hydroxy-azepanes were analysis based on their crystal structures. It was demonstrated the conformations with steric group substituted on theβor i position of the twist-chair form were slightly preferred. Based on the unique discovery of ammonium-driven diastereoisomerism in the crystal, a further NMR study and theoretical calculations were performed and presented a "TC₁-T₁-TB₁-TB₂-T₂-TC₂" step-wise mechanism of the conformational conversion. Finally, a general rule for predicting the prevalence conformations azepane-like seven membered rings and their transition pathway was proposed.In the eighth section, the experimental part for the preparation of more than 55 intermediates and target compounds was presented. Among them, 52 are novel compounds. Furthermore, four stereoisomers of 3-aryl-4-hydroxy-azepanes were elucidated by X-ray crystallography, their enantiomers excess were determined by chiral HPLC as well.