The compound N-piperidinyl-[8-chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide] (NESS 0327) was synthesized and evaluated for binding affinity toward cannabinoid CB 1 and CB 2 receptor. NESS 0327 exhibited a stronger selectivity for CB 1 receptor compared with, showing a much higher affinity for CB 1 receptor (K i ϭ 350 Ϯ 5 fM and 1.8 Ϯ 0.075 nM, respectively) and a higher affinity for the CB 2 receptor (K i ϭ 21 Ϯ 0.5 nM and 514 Ϯ 30 nM, respectively). Affinity ratios demonstrated that NESS 0327 was more than 60,000-fold selective for the CB 1 receptor, whereas SR 141716A only 285-fold. NESS 0327 alone did not produce concentration-dependent stimulation of guanosine 5Ј-O-(3-[ Interest in the pharmacology of cannabinoids (CBs) has rapidly increased after the cloning of cannabinoid receptors and the discovery of their endogenous ligand: arachidonylethanolamide (anandamide) (Devane et al., 1988(Devane et al., , 1992Munro et al., 1993). Two types of cannabinoid receptors, CB 1 and CB 2 , have been characterized, both of which have distinct anatomical distributions and ligand binding profiles. Cannabinoid CB 1 receptors are present in the central nervous system with the highest densities in the hippocampus, cerebellum, and striatum (Herkenham et al., 1990;Howlett, 1998), and to a lesser extent in several peripheral tissues. Cannabinoid CB 2 receptors seem to be predominantly located in peripheral tissues (Pertwee, 1997(Pertwee, , 1999Galiègue et al., 1995). Both receptors belong to the G protein-coupled family of receptors that negatively regulate adenylate cyclase and control the release of arachidonic acid (Howlett, 1995). Naturally occurring [⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) and ⌬ 8 -THC] and synthetic cannabinoid agonists CP 55,940, and WIN 55, produce a number of effects in mice (hypoactivity, catalepsy, hypothermia, and antinociception) that are collectively known as the tetrad of cannabinoidinduced behaviors (Abood and Martin, 1992;Compton et al., 1992Compton et al., , 1993. These behaviors are of a central origin and are thought to be mediated via the cannabinoid CB 1 receptor (Rinaldi-Carmona et al., 1994;Compton et al., 1996;Lichtman and Martin, 1997), whereas the CB 2 receptor may mediate some of the peripheral effects of ⌬ 9 -THC, such as immunosuppression (Martin, 1986).The cloning of CB 1 and CB 2 receptors and the subsequent development of selective tools have advanced the concept of Article, publication date, and citation information can be found at

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Mechanical properties of the vascular smooth muscle from normal and dystrophin-deficient (mdx) mice were examined. Changes in resting and developed tensions in response to stretch were recorded in isolated portal vein. The vascular segments were elongated in 5 % increments of the 'in situ' length (Lr) up to 1.30Lr. The resting length-tension curves in male mdxmice were similar to normal mice, while a marked decrease in the slope of the curve was noted in female mdx mice. These findings were not affected by atropine, phentolamine, tetrodotoxin or [Ca2+] in the surrounding media. At Lr, the tension of isolated portal vein was characterized by spontaneous synchronized uniform force waves in normal mouse. In contrast, in mdxmouse portal veins an irregular motor pattern characterized by desynchronized force waves with a decrease of amplitude and an increase in frequency was recorded. Extension of the length of the portal vein segment did not increase the spontaneous phasic activity developed in female mdx mice although this was noted with male mdx mice and normal mice. Experiments with chemical depolarizing agents indicated that spontaneous myogenic excitation activated the great majority of vascular smooth muscle cells in normal mouse portal vein, whereas in mdx mice only a reduced number of these cells were excited suggesting that in the mdx mouse the intercellular electronic coupling is altered. In conclusion this study provides the first description of the mechanical activities of portal vein longitudinal muscle and shows that in mdx mice the motor activity is severely disrupted.