Selective CB2 receptor agonists. Part 2: Structure–activity relationship studies and optimization of proline-based compounds

Riether, Doris; Zindell, Renée; Wu, Lijie; Betageri, Raj; Jenkins, James E.; Khor, Someina; Berry, Angela; Hickey, Eugene R.; Ermann, Monika; Albrecht, Claudia; Ceci, Angelo; Gemkow, Mark J.; Nagaraja, N.; Romig, Helmut; Sauer, Achim; Thomson, D. S.

doi:10.1016/j.bmcl.2014.12.019

Cited by 13 publications

(21 citation statements)

References 20 publications

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“…129,130 Proline analogs 116 and 117, developed by Boehringer Ingelheim Pharmaceuticals, are two of the most selective compounds reported to date with greater than 35,700-fold selectivity and 29,300fold selectivity, respectively. 131 Both of these demonstrated a dose-dependent reversal of hyperalgesia in a rat diabetic neuropathy model. outlook.…”

Section: Synthetic Classical Cannabinoidsmentioning

confidence: 99%

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Bow

Rimoldi

2016

Perspect Medicin Chem

112

111

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The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.

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Section: Synthetic Classical Cannabinoidsmentioning

confidence: 99%

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Bow

Rimoldi

2016

Perspect Medicin Chem

112

111

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“…Several proline derivatives were identified by a computer assisted drug design (CADD) approach based on a well-known series of CB2 receptor ligands by Hickey and co-workers [ 102 ]. Several ( S )-isomers showed full CB2 agonist activities with high potencies (picomolar range) and a CB2/CB1 selectivity ratio higher than 750, while the corresponding ( R )-isomers displayed a partial agonist profile with lower potencies toward the CB2 receptor.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationship of Cannabis Derived Compounds for the Treatment of Neuronal Activity-Related Diseases

et al. 2018

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Cannabis sativa active compounds are extensively studied for their therapeutic effects, beyond the well-known psychotropic activity. C. Sativa is used to treat different medical indications, such as multiple sclerosis, spasticity, epilepsy, ulcerative colitis and pain. Simultaneously, basic research is discovering new constituents of cannabis-derived compounds and their receptors capable of neuroprotection and neuronal activity modulation. The function of the various phytochemicals in different therapeutic processes is not fully understood, but their significant role is starting to emerge and be appreciated. In this review, we will consider the structure-activity relationship (SAR) of cannabinoid compounds able to bind to cannabinoid receptors and act as therapeutic agents in neuronal diseases, e.g., Parkinson’s disease.

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“…4H), 1.41 (H8, H9, 3b, m, 4H), 1.39 (H6, 3a, 3b, m, 2H), 0.96 (CH 3 , t-Bu, 3a, s, 9H), 0.92 (CH 3 , t-Bu, 3b, s, 9H). 13 C NMR (151 MHz, CDCl 3 ): δ/ppm 176.1 (CO, 3a), 175.6 (CO, 3b), 172.8 (CO, 3a), 172.6 (CO, 3b), 166.6 (CO, 3a), 165.9 (CO, 3b), 147.9 (Car, 3a), 147.8 (Car, 3b), 142.8 (Car, 3a), 141.1 (Car, 3b), 130.8, 129.2, 123.8, 123.6 (CHar, 3a, 3b), 59.9 (C1, 3a), 59.4 (C1, 3b), 58.8 (C2, 3a), 58.7 (C2, 3b), 56.0 (C6, 3a), 55.9 (C6, 3b), 52.5 (OMe, 3a), 52.2 (OMe, 3b), 52.2 (C5, 3a), 51.9 (C5, 3b), 31.6 (C7, 3a), 31.6 (C7, 3b), 31.6, 31.5, 31.4, 31.4, 30.9, 30.9 (CH 3 , t-Bu, 3a, 3b), 29.2 (C4, 3a), 29.1 (C4, 3b), 28.8, 28.6, 28.5, 28.4 (C8, C9, 3a, 3b), 24.6 (C3, 3a), 24.2 (C3, 3b…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

“…Cyclization can also be performed by intramolecular N -alkylation of an amide or by C–C bond formation . In addition to these cyclization strategies, several (3 + 2) and (4 + 1) cycloaddition/annulation reactions leading to the γ-lactam structure have also been designed …”

Section: Introductionmentioning

confidence: 99%

“…12 In addition to these cyclization strategies, several (3 + 2) and (4 + 1) cycloaddition/ annulation reactions leading to the γ-lactam structure have also been designed. 13 Furthermore, recognizing the potential for discovery of novel bioactive small molecules based upon the γ-lactam core structure, several research groups have presented interesting multicomponent or cascade approaches toward functionalized γ-lactams. 14−16 Multicomponent reactions (MCRs) were found to be an excellent tool to rapidly access a large and versatile drug-like chemical space to address the corresponding biological space.…”

Section: ■ Introductionmentioning

confidence: 99%

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Multicomponent Approach to a Library of N-Substituted γ-Lactams

et al. 2018

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The γ-lactam motif is often found in naturally occurring compounds with diverse biological activities. We prepared a 28-member library of N-substituted γ-lactams following a single-pot, three-component Ugi reaction comprising bifunctional building block, L-glutamic acid methyl ester. The reaction tolerates structurally diverse carbonyl and isocyanide components providing a robust access to functionalized γ-lactams. Antimicrobial susceptibility testing, including agar well diffusion assay, serial microdilution broth assay, and antibiofilm activity testing, identified a potent compound with antibiofilm activity against Staphylococcus aureus ATCC 6538.

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Selective CB2 receptor agonists. Part 2: Structure–activity relationship studies and optimization of proline-based compounds

Cited by 13 publications

References 20 publications

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Structure-Activity Relationship of Cannabis Derived Compounds for the Treatment of Neuronal Activity-Related Diseases

Multicomponent Approach to a Library of N-Substituted γ-Lactams

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