TheIn VivoEffects of the CB₁-Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice

Abstract

The CB PAM GAT229 reduces IOP in ocular hypertensive mice and enhanced CB-mediated IOP reduction when combined with subthreshold CB orthosteric ligands in normotensive mice. Administration of CB PAMs may provide a novel approach to reduce IOP with fewer of the disadvantages associated with orthosteric CB activation.

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation

“…Local increases of endocannabinoids at the site of pathology that are enough to potentate the actions of CB1 PAMs may be more desirable as a treatment paradigm; it would enable PAMs to be administered without requiring the addition of orthosteric agonists. Such was the case in models of neuropathic and inflammatory pain treated with GAT211 and ZCZ011 [35,36], and for intraocular pressure lowing in a mouse model of ocular hypertension, an effect which was absent in normotensive mice [50]. In our corneal hyperalgesia model, administration of GAT211 or GAT229 reduced corneal pain when combined with subthreshold ∆ 8 -THC, but not on their own.…”

Positive Allosteric Modulation of CB1 Cannabinoid Receptor Signaling Enhances Morphine Antinociception and Attenuates Morphine Tolerance Without Enhancing Morphine- Induced Dependence or Reward

“…Theoretically, an allosteric modulator affords better temporal and spatial resolution as it is only efficacious if the orthosteric site is occupied at the same time (Wootten et al, 2012), in contrast to an exogenous agonist which can activate the receptor independent of the presence of the endogenous ligand. Work from our laboratory and others suggest that CB 1 PAMs show anti-allodynic efficacy in preclinical models of ocular, inflammatory and neuropathic pain without producing the characteristic cannabimimetic side-effect profile (Ignatowska-Jankowska et al, 2015;Cairns et al, 2017;Slivicki et al, 2018b;Garai et al, 2020;Thapa et al, 2020). We demonstrated that the CB 1 PAM GAT211 suppressed inflammatory pain produced by intraplantar injection of complete Freund's adjuvant as well as chemotherapy-induced neuropathic pain produced by paclitaxel without producing tolerance (Slivicki et al, 2018b).…”

Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol‐dimethylheptyl at the type 1 and type 2 cannabinoid receptors

“…The risk of adverse effects for allosteric modulators is reduced because allosteric compounds lack intrinsic agonism and can only modify the effects of endogenous or co‐administered orthosteric ligands (Christopoulos and Kenakin, ; Wootten et al ., ). In the case of cannabinoid receptors, allosteric modulators may be especially useful because the psychomimetic and depressant effects of orthosteric ligands limit their potential therapeutic utility (Ignatowska‐Jankowska et al ., ; Cairns et al ., ; Slivicki et al ., ).…”