Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

Abstract

The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a–d and 6a–d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(−)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(−)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.

Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation

“…We also included 2a, DTG ( 9), (+)-pentazocine (10), BD-1063 (11), DAMGO (13), naltrindole ( 14) and ()-U50,488 (15) as internal controls that were tested with the same membrane homogenates of the hybrid compounds under investigation (Figure S1). All the reference compounds showed Ki values for σ1 and σ2 receptors and the three opioid receptors comparable to those reported in previous studies [27][28][29][30][31][32]. It is worth pointing out that compounds 1a,b were devoid of affinity for either σ receptors or the three opioid receptors examined.…”

LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief

“…The LP1 analogue 3 ( Figure 2 ), lacking the amide functionality and with a tertiary N -ethylamine group as flexible spacer supporting the phenyl ring, exhibited a selective MOPr agonist profile [ 45 ]. In vitro a K i MOR of 6.1 nM in a competitive binding assay, and an IC 50 value of 11.5 nM and an I max of 72% in measurement of the cyclic adenosine monophosphate ( c AMP) accumulation in human embryonic kidney (HEK293) cells stably expressing MOPr, were detected.…”

“… a [ 41 ]; e [ 42 ]; b [ 43 ]; c [ 45 ]; d [ 47 ]; GPI guinea pig ileum, MVD mouse vas deferens. Data reproduced with permission from a Copyright 2010, Elsevier, e Copyright 2012, Elsevier, b Copyright 2016, Elsevier, d Copyright 2017, Elsevier.…”

Synthesis and Structure-Activity Relationships of (−)-cis-N-Normetazocine-Based LP1 Derivatives

“…However, this bulkier substituent switched the efficacy profile from agonism to antagonism [ 18 ]. The presence of a second positive charge, as well as the shortening of the N -substituent spacer, obtained through the insertion of secondary and tertiary ethylamino or propylamino side chains, led to benzomorphan-based compounds able to address the ligand–opioid receptor interaction, mainly at MOR and KOR [ 19 ]. Recently, we have also reported the insertion at the basic nitrogen of a shorter and more flexible ethyl spacer with H-bonding groups at carbon 2 as a successful strategy to improve MOR and DOR affinity [ 20 ].…”

“…In this study, we extended our structure–activity relationships (SARs) [ 14 , 18 , 19 , 20 ] and evaluated the effects of para electron-donating or -withdrawing groups insertion in the LP1 phenyl ring ( 10 – 13 , Figure 2 ). Moreover, the employment of phenyl ring surrogates with an increased steric hindrance (using indoline, tetrahydroquinoline, and diphenylamine functionalities) in the N -substituent ( 14 – 16 , Figure 2 ) was also assessed.…”