Benzomorphan scaffold for opioid analgesics and pharmacological tools development: A comprehensive review

Turnaturi, Rita; Marrazzo, Agostino; Parenti, Carmela; Pasquinucci, Lorella

doi:10.1016/j.ejmech.2018.02.046

Cited by 24 publications

(18 citation statements)

References 43 publications

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“…Benzomorphan, with morphan, phenylmorphan and phenylpiperidine, originate from morphine structure simplification [ 34 ]. The benzomorphan nucleus, aliases 2,6-methano-3-benzazocin-8-ol, provide a rigid backbone for probing the pharmacophoric requirements in opioid receptor interaction, represented by the aromatic ring, the saturated or morphan segment, and the nitrogen substituent.…”

Section: Dual-target Benzomorphan-based Ligands Lp1 and Lp2mentioning

confidence: 99%

“…In the rigid benzomorphan scaffold, the importance of (a) basic nitrogen and (b) phenolic group, at a reciprocal distance comparable to similar functional groups of Tyr 1 of endogenous opioid peptides, was highlighted [ 34 ]. Moreover, basic nitrogen substituents and modifications in the phenolic group are critical for opioid receptor recognition.…”

Section: Dual-target Benzomorphan-based Ligands Lp1 and Lp2mentioning

confidence: 99%

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

et al. 2021

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Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule-multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described.

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Section: Dual-target Benzomorphan-based Ligands Lp1 and Lp2mentioning

confidence: 99%

Section: Dual-target Benzomorphan-based Ligands Lp1 and Lp2mentioning

confidence: 99%

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

et al. 2021

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“…The cis -(−)- N -normetazocine nucleus, derived by structure-activity relationships (SARs) during morphine skeleton simplification [ 1 , 2 ], has been the subject of medicinal chemistry exploration for the development of new drugs and pharmacological tools to explore opioid pharmacology in vitro and in vivo [ 3 ]. This nucleus is a rigid scaffold able to support the phenolic ring and the basic nitrogen in a correct conformation mimicking the tyramine of opioid peptides [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…2 Truncated systems containing a benzomorphan scaffold (Figure 1) have proven to be particularly useful in this regard. 3,4 A number of synthetic routes have been developed for the synthesis of benzomorphans. 5 Among them, those using the acid-catalysed intramolecular FriedelÀCrafts cyclisation-of benzyl functionalised piperidines with hydroxyl or C=C double moieties-to form ring B of the benzomorphan skeleton have been applied successfully to the synthesis of several active compounds (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Asymmetric synthesis of (1R,5S)‐2‐methyl‐6,7‐benzomorphan via Aza‐Prins reaction

et al. 2021

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1R,5S)-2-Methyl-6,7-benzomorphan has been synthesised from (R)-(benzyloxy) (phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf) 3 promoted Aza-Prins reaction with N-tosylhomoallylamine afforded an 88/12 mixture of 6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to enantiomerically pure (2S,4S)-2-benzyl-1-methylpiperidin-4-ol via a highyielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed intramolecular FriedelÀCrafts cyclisation of the piperidinol afforded (1R,5S)-2-methyl-6,7-benzomorphan in five steps with a yield of 25%.

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Benzomorphan scaffold for opioid analgesics and pharmacological tools development: A comprehensive review

Cited by 24 publications

References 43 publications

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

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

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

Asymmetric synthesis of (1R,5S)‐2‐methyl‐6,7‐benzomorphan via Aza‐Prins reaction

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