Published: September 08, 2011 Copyright r 2011 American Chemical Society and American Society of Pharmacognosy 2019 dx.doi.org/10.1021/np200500p | J. Nat. Prod. 2011, 74, 2019–2022 NOTE pubs.acs.org/jnp Bioactive Prenylogous Cannabinoid from Fiber Hemp (Cannabis sativa) Federica Pollastro, † Orazio Taglialatela-Scafati, ‡ Marco Allar  a, § Eduardo Mu~ noz, ^ Vincenzo Di Marzo, § Luciano De Petrocellis,* ,||,§ and Giovani Appendino* ,† † Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universit  a del Piemonte Orientale, Via Bovio 6, 28100, Novara, Italy ‡ Dipartimento di Chimica delle Sostanze Naturali, Universit  a di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy § Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy ^ Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Medicina, Universidad de C ordoba, Avenida de Men endez Pidal s/n, 14004 C ordoba, Spain ) Endocannabinoid Research Group, Institute of Cybernetics, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy b S Supporting Information C annabinoids are a class of meroterpenoids typical of Canna- bis sativa L. (hemp, Cannabinaceae). 1 With the exception of cannabigerol (CBG, 1), which also occurs in an African Helichrysum species, 2 C. sativa represents the sole natural source of these compounds. Cannabinoids are made up by an isoprenyl moiety bound to a resorcinyl-type polyketide unit. Due to postcoupling, mainly oxidative, modifications, there is no short- age of structural variations in the prenyl moiety of cannabinoids, but variance in the cannabinoid biogenetic building blocks has so far been reported only in the resorcinyl moiety, which can derive from either a hepta- or a hexaketide precursor, resulting in compounds with an n-pentyl (cannabinoid sensu stricto) or a n-propyl (cannabidivarin) alkyl moiety. Conversely, the isopre- nyl moiety is of the monoterpene type in all the more than 100 cannabinoids characterized so far. 1 Owing to the presence of high concentrations of the psycho- tropic agent Δ 9 -THC (2), biomedical attention on C. sativa has so far mainly focused on varieties of this plant used for recrea- tional purposes (marijuana), while the pharmacological potential of fiber hemp is still largely untapped. This observation is surprising, since certain biological properties of THC are shared also by nonpsychotropic cannabinoids, 1,3 suggesting that some pharmacologically useful activities of C. sativa, such as antibac- terial, anti-inflammatory, and antipsoriasis actions, could be dissected from its psychotropic potential. Our interest in this area has focused on chemotypes derived from Carmagnola, a variety of exceptional length (up to 56 m) once extensively grown in Northern Italy especially for the production of naval ropes. 4 In previous work, we have characterized some unique cannabinoids and phenolics from relatively polar fractions of these hemp strains. 5 During the manipulation of crude acetone extracts from the variety Carma, a hemp chemotype character- ized by the accumulation of CBG (1) and cannabidiol (CBD, 3) in a ca. 6:1 ratio, 5 we observed the formation of a copious waxy precipitate, from which sesquicannabigerol (sesqui-CBG, 4), a lipophilic cannabinoid of a novel biogenetic type, was obtained. The sesquicannabinoid 4 is a minor constituent (ca. 100 mg/kg Received: June 20, 2011 ABSTRACT: The waxy fraction from the variety Carma of fiber hemp (Cannabis sativa)afforded the unusual cannabinoid 4, identified as the farnesyl prenylogue of cannabigerol (CBG, 1) on the basis of its spectroscopic properties. A comparative study of the profile of 4 and 1 toward metabotropic (CB 1 , CB 2 ) and ionotropic (TRPV1, TRPV2, TRPM8, TRPA1) targets of phytocannabinoids showed that prenylogation increased po- tency toward CB 2 by ca. 5-fold, with no substantial difference toward the other end-points, except for a decreased affinity for TRPM8. The isolation of 4 suggests that C. sativa could contain yet-to-be-discovered prenylogous versions of medicinally rele- vant cannabinoids, for which their biological profiles could offer interesting opportunities for biomedical exploitation.