ChemInform Abstract: Soft Cannabinoid Analogues as Potential anti‐Glaucoma Agents.

Buchwald, A.; Derendorf, H; F, Ji; Nagaraja, N Y; Wu, Whei Mei; Bodor, Nicholas

doi:10.1002/chin.200031153

Cited by 5 publications

(15 citation statements)

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“…19 In a different approach, ester group containing N -benzyl-benzopyrones that share some structural features with Nabitan, a cannabinoid lead developed at Abbott laboratories, were synthesized. 12,20 Although CB receptor binding affinities, or cannabinoid related behavioral pharmacology of these compounds are not reported, in vivo testing suggests that they possess moderate intraocular pressure lowering activity. 12 …”

Section: Introductionmentioning

confidence: 99%

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Controlled-Deactivation Cannabinergic Ligands

et al. 2013

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We report an approach for obtaining novel cannabinoid analogs with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (−)-Δ8-THC analogs. We have sought to introduce benzylic substituents alpha to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl and 1'-cyclobutyl analogs exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogs were shown to be potent CB1 receptor agonists and exhibit CB1-mediated hypothermic and analgesic effects.

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Section: Introductionmentioning

confidence: 99%

“…12,20 Although CB receptor binding affinities, or cannabinoid related behavioral pharmacology of these compounds are not reported, in vivo testing suggests that they possess moderate intraocular pressure lowering activity. 12 …”

Section: Introductionmentioning

confidence: 99%

Controlled-Deactivation Cannabinergic Ligands

et al. 2013

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“…17 In addition, some "Nabitan" inspired N-benzylbenzopyrone esters were reported to possess moderate intraocular pressure lowering activity. 6,18 However, there are no reports linking these in vivo effects with cannabinergic activity.…”

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confidence: 99%

“…Classical cannabinoids including the phytocannabinoid (−)-Δ 9 -tetrahydrocannabinol [(−)-Δ 9 -THC, 1 , Figure ] and its congeners produce most of their biological effects by modulating the cannabinoid receptors CB1 and CB2. − These two GPCRs are currently being targeted for an array of conditions including neurodegeneration, inflammation, pain, glaucoma, and eating disorders. − Only a limited number of cannabinergic drugs have been approved to date. However, the widespread use of cannabinoid agonists in therapy has been hindered due to the undesirable side effects associated with CB1 receptor activation/deactivation as well as poor pharmacokinetic/pharmacodynamic (PK/PD) properties .…”

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confidence: 99%

“…Earlier efforts to develop soft-cannabinoids by incorporating an enzymatically labile ester group into a biphenyl template resulted in compounds with very low binding affinities for the CB receptors . In addition, some “Nabitan” inspired N -benzyl-benzopyrone esters were reported to possess moderate intraocular pressure lowering activity. , However, there are no reports linking these in vivo effects with cannabinergic activity.…”

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confidence: 99%

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C-Ring Cannabinoid Lactones: A Novel Cannabinergic Chemotype

Sharma

Nikas

Guo

et al. 2014

ACS Med. Chem. Lett.

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As a part of our controlled-deactivation ligand development project, we recently disclosed a series of (-)-Δ(8)-tetrahydrocannabinols (THCs) with a metabolically labile ester group at the 2'-position of the side chain. Now, we have replaced the C-ring in the classical THC structure with a hydrolyzable seven-membered lactone. One of the synthesized analogues binds with high affinity to the CB1 receptor (K i = 4.6 nM) and exhibits much lower affinities for the mCB2 and the hCB2. Also, in vitro functional characterization found the compound to be an agonist at rCB1. Consistent with our rational design, the lead cannabinergic lactone identified here is susceptible to metabolic inactivation by plasma esterases, while the respective acid metabolite is inactive at CB receptors. These results are highlighted with molecular modeling of the two regiosomeric lactones.

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Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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ChemInform Abstract: Soft Cannabinoid Analogues as Potential anti‐Glaucoma Agents.

Cited by 5 publications

References 0 publications

Controlled-Deactivation Cannabinergic Ligands

Controlled-Deactivation Cannabinergic Ligands

C-Ring Cannabinoid Lactones: A Novel Cannabinergic Chemotype

Retrometabolism‐Based Drug Design and Targeting

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