Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid Manuel López-Ortíz a , Andrea Herrera-Solís b , Axel Luviano-Jardón a , Nidia Reyes-Prieto b , Ivan Castillo c , Ivan Monsalvo a , Patricia Demare a , Mónica Méndez-Díaz b , Ignacio Regla a,c, * , Oscar Prospéro-García b, * a Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Batalla del 5 de Mayo y Fuerte de Loreto, Iztapalapa 09230, Mexico, D.F., Mexico b Laboratorio de Canabinoides, Grupo de Neurociencias, Facultad de Medicina, UNAM, Circuito Exterior, Ciudad Universitaria, 04510 Mexico, D.F., Mexico c Instituo de Química, UNAM, Circuito Exterior, Ciudad Universitaria, 04510 Mexico, D.F., Mexico article info Article history: Received 5 March 2010 Revised 14 April 2010 Accepted 16 April 2010 Available online 21 April 2010 Keywords: Cannabinoids Core temperature Pain regulation Sleep-waking cycle abstract Endocannabinoids (eCBs) are endogenous neuromodulators of synaptic transmission. Their dysfunction may cause debilitating disorders of diverse clinical manifestation. For example, drug addiction, lack of sex desire, eating disorders, such as anorexia or bulimia and dyssomnias. eCBs also participate in the regulation of core temperature and pain perception. In this context, it is important to recognize the utility of cannabinoid receptor 1 (CB1R) agonists, natural as D 9 -tetrahydrocannabinol (THC) or synthetic as Nabilone as useful drugs to alleviate this kind of patients’ suffering. Therefore, we have developed a new drug, (R,Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-yl phenylacetate (PhAR-DBH-Me), that appears to bind and activate the CB1R. This diazabicyclic amide was synthesized from phenylacetylricinoleic acid and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane. To test its cannabinergic properties we evaluated its effects on core temperature, pain perception, and the sleep- waking cycle of rats. Results indicate that 20 and 40 mg/kg of PhAR-DBH-Me readily reduced core temperature and increased pain perception threshold. In addition, 20 mg/kg increased REM sleep in otherwise normal rats. All these effects were prevented or attenuated by AM251, a CB1R antagonist. Place preference conditioning studies indicated that this molecule does not produce rewarding effects. These results strongly support that PhAR-DBH-Me possesses cannabinoid activity without the reinforcement effects. Ó 2010 Elsevier Ltd. All rights reserved. Endocannabinoids (eCBs) are molecules synthesized by neurons of all mammalians and insects known. 1 eCBS modulate the synap- tic transmission participating in the generation of several types of behavior. 2 Therefore, their dysfunction may cause debilitating dis- orders of diverse clinical manifestation. For example, drug addic- tion, 3 lack of sex desire and eating disorders, 4 such as anorexia or bulimia 5 and dyssomnias. 6 Additionally, the activation of the can- nabinoid receptor 1 (CB1R) modulates pain perception and core temperature. 7 Mounting evidence indicates that in schizophrenia eCBs may be dysfunctional. 8 Marijuana derivatives, such as D 9 -tetrahydrocannabinol (THC, Fig. 1) commercially available as Dronabinol Ò or THC plus cannabi- diol (Sativex Ò ) and several synthetic compounds as Nabilone (Cesamet Ò ), among others, produce several therapeutic effects. 9,10 For example, they are appetite stimulants in patients suffering from wearing-off caused by acquired immunodeficiency syndrome Scheme 1. Chemical synthesis of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (1) from trans-4-hydroxy-(S)-proline. Reagents and conditions: (a) TsCl, Na 2 CO 3 , H 2 O, 94%; (b) NaBH 4 , BF 3 Et 2 O, THF, 85%; (c) TsCl, C 5 H 5 N, toluene, 20 h, 83%; (d) PhCH 2 NH 2 , toluene, reflux, 96%; (e) HBr 40%, 96%; (f) HCO 2 H, HCOH, MeOH, reflux, 73%; (g) H 2 , Pd/C, MeOH 80%. 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.04.074 * Corresponding authors. Tel.: +52 55 5623 0795 (I.R.); +52 55 5623 2509 (O.P.-G.). E-mail addresses: regla@unam.mx (I. Regla), opg@unam.mx (O. Prospéro- García). Figure 1. Chemical structures of THC and Nabilone. Bioorganic & Medicinal Chemistry Letters 20 (2010) 3231–3234 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl