The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

Nikas, Spyros P.; Grzybowska, Jolanta; Papahatjis, Demetris P.; Charalambous, Avgui; Banijamali, Ali R.; Chari, Ravi; Fan, Pusheng; Kourouli, Therapia; Lin, Sonyuan; Nitowski, Albert J.; Marciniak, Gilbert; Guo, Yan; Li, Xiuyan; Wang, Chia-Lin J.; Makriyannis, Alexandros

doi:10.1208/aapsj060430

Cited by 29 publications

(52 citation statements)

References 33 publications

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“…Optimal activity is obtained with a seven or eight carbon length substituted with 1′,1′-or 1′,2′-dimethyl groups as was first demonstrated by Adams (e.g. 2) [52][53][54], while incorporation of halogen, cyano or azido group at the end of the side chain enhances CB1 affinity [55][56][57][58][59][60]. Thus, AM087 (3a) and O-581 (3b) bearing bromo and cyano substituents respectively at the end of the dimethylpentyl side chain exhibit subnanomolar affinities for the CB1 receptor.…”

Section: Classical Cannabinoidsmentioning

confidence: 97%

CB1 Cannabinoid Receptor Ligands

Thakur¹,

Nikas²,

Makriyannis³

2005

MRMC

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The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

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Section: Classical Cannabinoidsmentioning

confidence: 97%

CB1 Cannabinoid Receptor Ligands

Thakur¹,

Nikas²,

Makriyannis³

2005

MRMC

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“…Structure–activity relationship (SAR) studies with classical cannabinoids have shown that the C3 alkyl chain lengths and ω -substitutions modulate ligand affinity. Also, incorporation of a C1′ -gem-dimethyl group affects the conformational properties of the alkyl chain and leads to notable enhancement in potency and efficacy 8–11 . Unlike Δ 9 -THC, which has a shorter alkyl chain ( n -pentyl), our results show that longer alkyl chains coupled with a C1′ -gem-dimethyl group allow extended interactions with CB 1 , while the C1′ -gem-dimethyl group forms hydrophobic interactions with Phe200 3.36 , Leu359 6.51 and Met363 6.55 (Fig.…”

mentioning

confidence: 99%

Crystal structures of agonist-bound human cannabinoid receptor CB1

Hua

Vemuri

Nikas

et al. 2017

Nature

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419

526

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The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC)1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1–agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state2, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a ‘twin toggle switch’ of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros–Weinstein numbering3) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

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“…41 To explore the structure activity relationships and the effect of halogen substitution we synthesized some derivatives possessing a chlorine atom or a trifluoromethyl group in the para position of the styryl group and compared their affinities for the cannabinoid receptors (CB 1 and CB 2 ). H NMR spectra of 3a-d and 4a-f show a singlet at δ H 10.39-10.83 ppm due to the OH-2' proton resonance, which is absent in the spectra of compounds 5a-d and 6a-f.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and pharmacological evaluation of new (E)- and (Z)-3-aryl-4-styryl-1H-pyrazoles as potential cannabinoid ligands

Silva¹,

Silva

Pinto³

et al. 2010

Arkivoc

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New (Z)-and (E)-1-alkyl-3-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles and (Z)-and (E)-3(5)-(2-alkyloxyphenyl)-4-styryl-1H-pyrazoles were prepared by alkylation of (Z)-and (E)-3(5)-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles with a long chain alkyl bromide in basic medium. The affinity of these alkylated pyrazoles to both human CB 1 and CB 2 type cannabinoid receptors was evaluated. The results showed that some of them exhibit affinity towards CB 1 cannabinoid receptors in the nanomolar range.

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The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

Cited by 29 publications

References 33 publications

CB1 Cannabinoid Receptor Ligands

CB1 Cannabinoid Receptor Ligands

Crystal structures of agonist-bound human cannabinoid receptor CB1

Synthesis and pharmacological evaluation of new (E)- and (Z)-3-aryl-4-styryl-1H-pyrazoles as potential cannabinoid ligands

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