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The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators.
Neuropharmacology. 2017 Oct; 125:365-375.N

Abstract

While allosteric modulators of the cannabinoid type-1 receptor (CB1) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB1 allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB1, blocking THC's effects in vitro and in vivo, highlighting the potential of CB1 allosteric modulators for treatment of cannabis intoxication. We investigated the pharmacological effects of PSNCBAM-1 and two structural analogs, RTICBM-15 and -28, as well as pregnenolone, in both signaling and behavioral assays including [35S]GTPγS binding, the cannabinoid tetrad and drug discrimination. While the CB1 allosteric modulator PSNCBAM-1 attenuated THC-induced anti-nociception and its structural analog RTICBM-28 reduced THC's potency in drug discrimination, most cannabinoid effects in mice were unaffected. In contrast to the mouse studies, PSNCBAM-1 and analogs insurmountably antagonized CP55,940- and THC-stimulated [35S]GTPγS binding and exhibited negative binding cooperativity with [3H]SR141716 with similar apparent affinities. Notably, RTICBM-28, which contains a cyano substitution at the 4-chlorophenyl position of PSNCBAM-1, exhibited enhanced binding cooperativity with CP55,940. In contrast to previous findings, pregnenolone did not block THC's effects in drug discrimination or [35S]GTPγS. These data further highlight the difficulty in translating pharmacological effects of CB1 allosteric modulators in vivo but confirm the established pharmacology of PSNCBAM-1 and analogs in molecular assays of CB1 receptor function.

Authors+Show Affiliations

RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA. Electronic address: tgamage@rti.org.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28803965

Citation

Gamage, Thomas F., et al. "The Great Divide: Separation Between in Vitro and in Vivo Effects of PSNCBAM-based CB1 Receptor Allosteric Modulators." Neuropharmacology, vol. 125, 2017, pp. 365-375.
Gamage TF, Farquhar CE, Lefever TW, et al. The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators. Neuropharmacology. 2017;125:365-375.
Gamage, T. F., Farquhar, C. E., Lefever, T. W., Thomas, B. F., Nguyen, T., Zhang, Y., & Wiley, J. L. (2017). The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators. Neuropharmacology, 125, 365-375. https://doi.org/10.1016/j.neuropharm.2017.08.008
Gamage TF, et al. The Great Divide: Separation Between in Vitro and in Vivo Effects of PSNCBAM-based CB1 Receptor Allosteric Modulators. Neuropharmacology. 2017;125:365-375. PubMed PMID: 28803965.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators. AU - Gamage,Thomas F, AU - Farquhar,Charlotte E, AU - Lefever,Timothy W, AU - Thomas,Brian F, AU - Nguyen,Thuy, AU - Zhang,Yanan, AU - Wiley,Jenny L, Y1 - 2017/08/10/ PY - 2017/04/27/received PY - 2017/07/25/revised PY - 2017/08/09/accepted PY - 2017/8/15/pubmed PY - 2018/6/13/medline PY - 2017/8/15/entrez KW - Allosteric modulation KW - Behavioral KW - Cannabinoids KW - Receptor binding KW - Signaling SP - 365 EP - 375 JF - Neuropharmacology JO - Neuropharmacology VL - 125 N2 - While allosteric modulators of the cannabinoid type-1 receptor (CB1) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB1 allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB1, blocking THC's effects in vitro and in vivo, highlighting the potential of CB1 allosteric modulators for treatment of cannabis intoxication. We investigated the pharmacological effects of PSNCBAM-1 and two structural analogs, RTICBM-15 and -28, as well as pregnenolone, in both signaling and behavioral assays including [35S]GTPγS binding, the cannabinoid tetrad and drug discrimination. While the CB1 allosteric modulator PSNCBAM-1 attenuated THC-induced anti-nociception and its structural analog RTICBM-28 reduced THC's potency in drug discrimination, most cannabinoid effects in mice were unaffected. In contrast to the mouse studies, PSNCBAM-1 and analogs insurmountably antagonized CP55,940- and THC-stimulated [35S]GTPγS binding and exhibited negative binding cooperativity with [3H]SR141716 with similar apparent affinities. Notably, RTICBM-28, which contains a cyano substitution at the 4-chlorophenyl position of PSNCBAM-1, exhibited enhanced binding cooperativity with CP55,940. In contrast to previous findings, pregnenolone did not block THC's effects in drug discrimination or [35S]GTPγS. These data further highlight the difficulty in translating pharmacological effects of CB1 allosteric modulators in vivo but confirm the established pharmacology of PSNCBAM-1 and analogs in molecular assays of CB1 receptor function. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28803965/The_great_divide:_Separation_between_in_vitro_and_in_vivo_effects_of_PSNCBAM_based_CB1_receptor_allosteric_modulators_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30375-1 DB - PRIME DP - Unbound Medicine ER -