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PubMed1996

Improvement of insulin sensitivity and dyslipidemia with a new alpha-glucosidase inhibitor, voglibose, in nondiabetic hyperinsulinemic subjects.

This study was undertaken to investigate the effect of voglibose, a new alpha-glucosidase inhibitor, on glucose and lipid metabolism in nondiabetic hyperinsulinemic subjects. Sixteen nondiabetic subjects with hyperinsulinemia participated in the study. They were divided into two groups of eight subjects with normal (NGT) and impaired (IGT) glucose tolerance. A meal tolerance test and a 75-g oral glucose tolerance test (OGTT) were performed at the beginning (baseline phase) and end (treatment phase) of the 12-week treatment. Serum lipid levels were measured every 4 weeks throughout the treatment phase and follow-up phase (8 weeks). All patients received 1 0.2-mg tablet of voglibose before each test meal (3 tablets per day). We also measured insulin sensitivity using a steady-state plasma glucose (SSPG) method in eight normotensive hyperinsulinemic subjects and in eight age- and body mass index (BMI)-matched control subjects before and after the drug treatment. Voglibose significantly decreased the responses of plasma glucose and insulin on the meal tolerance test. The area under the curve for 2-hour insulin during the 75-g OGTT decreased after treatment, whereas that for 2-hour glucose did not change before and after treatment. SSPG was reduced after treatment, indicating improvement of insulin sensitivity. Moreover, treatment with voglibose resulted in a significant decline of triglyceride level and an elevation of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1. These values returned to near-baseline levels after the drug was discontinued. Consequently, we conclude that this agent not only has a direct hypoglycemic effect through decreased absorption of carbohydrate, but also a hypoinsulinemic and hypolipidemic effect via improved insulin sensitivity.

Blood Glucose↗
PubMed2000

Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: I. in vivo electrophysiological studies in the rat.

The effect of a 21-day treatment with the dual 5-HT and NE reuptake blocker venlafaxine (delivered s.c. by osmotic minipumps) was assessed on the time required for a 50% recovery (RT(50)) of the firing activity of dorsal hippocampus CA(3) pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NE. The RT(50) values for 5-HT were increased by both 10 and 40 mg/kg/day regimens of venlafaxine, whereas those for NE were increased only by the 40 mg/kg/day regimen, indicative of a greater potency of venlafaxine in blocking 5-HT reuptake. The sensitivity of the postsynaptic 5-HT(1A) and alpha(2)-adrenergic receptors was altered by neither regimen of venlafaxine. Using a paradigm by which the 5-HT(1A) antagonist WAY 100635 can induce a disinhibition of firing activity of CA(3) pyramidal neurons, it was demonstrated that the high, but not the low, dose of venlafaxine led to an enhanced tonic activation of postsynaptic 5-HT(1A) receptors in the dorsal hippocampus. The duration of the suppressant effect of the firing activity of CA(3) hippocampus pyramidal neurons produced by the electrical stimulation of the ascending 5-HT pathway was significantly reduced when the frequency of the stimulation was enhanced from 1 Hz to 5 Hz in control rats and in rats treated with 10 mg/kg/day, but not with 40 mg/kg/day of venlafaxine. Hence, venlafaxine induced a desensitization of the terminal 5-HT(1B) autoreceptor only at the high dose. A 2-day treatment with 10 mg/kg/day of venlafaxine induced a suppression of the firing activity of 5-HT neurons of the dorsal raphe. The firing activity of these neurons was back to control level in rats that had been treated for 21 days with the same dose of venlafaxine. The suppressant effect of the i.v. administration of the 5-HT autoreceptor agonist LSD on the firing activity of dorsal raphe 5-HT neurons was reduced in rats that had been treated for 21 days with 10 mg/kg/day of venlafaxine. A 2-day treatment with 40 mg/kg/day of venlafaxine, unlike the 10 mg/kg/day regimen, induced a marked suppression of the firing activity of locus coeruleus NE neurons. However, in contrast to 5-HT neurons, NE neurons did not recover their firing activity after a 21-day treatment. Taken together, the results from this study indicate that the low dose of venlafaxine blocked selectively the reuptake of 5-HT, whereas the high dose blocked the reuptake of both 5-HT and NE. Moreover, an enhancement of serotonergic neurotransmission by venlafaxine was only achieved under conditions whereby the desensitization of the terminal 5-HT(1B) autoreceptor is appended to that of the somatodendritic 5-HT(1A) receptor.

Animals↗
PubMed2000

Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat.

The effects of long-term administrations of a low (10 mg/kg/day) and a high (40 mg/kg/day) dose of the dual 5-HT and NE reuptake inhibitor venlafaxine (delivered s.c. by osmotic minipumps for 21 days) were assessed on the electrically-evoked release of tritium from hippocampal slices preloaded with either [(3)H]5-HT or [(3)H]NE, 48 h after the removal of the minipump. The high, but not the low, dose regimen of venlafaxine enhanced the electrically-evoked release of [(3)H]5-HT while treatment with the high dose of venlafaxine failed to alter the electrically-evoked release of [(3)H]NE. The inhibitory effect of the 5-HT(1B) agonist CP 93,129 on the electrically evoked release of [(3)H]5-HT was unaltered by the low dose regimen of venlafaxine while it was attenuated in rats treated with the high dose of venlafaxine, indicative of a functional desensitization of the terminal 5-HT(1B) autoreceptor. Unexpectedly, neither regimen of venlafaxine altered the inhibitory effect of UK 14,304 on the electrically evoked release of both [(3)H]5-HT and [(3)H]NE, indicating that neither the alpha(2)-adrenergic auto- nor heteroreceptors were desensitized. Finally, the functions of the 5-HT and NE reuptake process were assessed. None of the treatment regimens altered the basal uptake of [(3)H]5-HT from hippocampal or mesencephalic slices nor that of [(3)H]NE from hippocampal slices. Finally, the enhancing effect of 1 microM of paroxetine in the perfusion medium on the electrical release of [(3)H]5-HT was unaltered in hippocampal slices prepared from rats that had been treated for 21 days with 40 mg/kg/day of venlafaxine. Taken together, these results indicate that, in terms of alteration of the sensitivity of the terminal 5-HT(1B) autoreceptor, alpha(2)-adrenergic auto-and heteroreceptors, the effects of long-term administration of venlafaxine are no different than those observed with classical SSRI's.

Adrenergic alpha-Agonists↗
PubMed2003

Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats.

Compounds that block both serotonin (5-HT) and norepinephrine (NE) transporters have been proposed to have improved antidepressant efficacy. We compared the ability of four dual transporter inhibitors-chlorimipramine, duloxetine, milnacipran and venlafaxine-to block monoamine transporters in vitro and in vivo and increase extracellular monoamines in rat brain. Inhibition of radioligand binding to clonal human monoamine transporters in vitro and in vivo in rats was determined. Extracellular concentrations of 5-HT and NE in rat prefrontal cortex (PFC) were quantified using the microdialysis technique. All compounds blocked binding to human 5-HT and NE transporters, although chlorimipramine and venlafaxine had markedly greater affinity for 5-HT than NE transporters. In vivo, chlorimipramine and duloxetine potently blocked both transporters, milnacipran blocked both with lower potency and venlafaxine only blocked the 5-HT transporter. Chlorimipramine and duloxetine increased robustly and approximately equally monoamine extracellular concentrations. Milnacipran produced only small increases in NE, whereas venlafaxine increased 5-HT markedly at the lower doses and both monoamines at high doses. Thus, the dual transporter inhibitors blocked 5-HT and NE transporters in vitro and in vivo with varying potency. Chlorimipramine, duloxetine, and high dose venlafaxine acted as dual transporter inhibitors in rat PFC and increased extracellular concentrations of the monoamines, indicating functional dual transporter inhibition.

Adrenergic Uptake Inhibitors↗
PubMed1996

Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.

Animals↗
PubMed1999

Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors.

Oleamide (cis-9,10-octadecenoamide) is an endogenous brain lipid which has been suggested to induce sleep in experimental animals. The mechanism of action is unclear but shares many of the characteristics of endogenous cannabinoids such as anandamide and has been shown to enhance in vitro responses to 5-HT and GABA. In the present study we investigated the effects of oleamide on two motor behaviours, back muscle contractions (BMC) and wet-dog shakes (WDS) induced in rats by treatment with the 5-HT2 receptor agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride). We then examined the potential involvement of CB1 cannabinoid receptors in the responses to oleamide and the mechanism of interaction between CB1 and 5-HT2 receptors. Oleamide and the cannabinoid receptor agonist HU210 (6aR)-trans-3-(1,1-dimethylheptyl)6a,7,10,10a-tetrahydro-1-h ydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol) produced a hypolocomotion which was prevented by the CB1 antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride). Despite having no effect alone, oleamide and HU210 potentiated BMC induced by treatment with DOI. SR141716A alone did not affect the response to DOI but it blocked the potentiations caused by oleamide or HU210. WDS were unaffected by oleamide and slightly reduced by HU210. In vitro, oleamide and HU210 enhanced the high affinity binding of 5-HT to 5-HT2 receptors on rat cerebral cortex membranes labelled with 3H-ketanserin. Neither agent, however, altered 5-HT-stimulated phosphoinositide hydrolysis in rat cerebral cortex slices. Oleamide occupied CB1 cannabinoid receptors on rat brain membranes labelled with 3H-CP55940 with an IC50 of 10 microM. The data presented are consistent with oleamide acting via a cannabinoid recognition site to enhance 5-HT2 receptor function in vivo. The mechanism of the modulation is still unclear but it does not appear to involve a potentiation of 5-HT2 receptor-stimulated phosphoinositide hydrolysis.

Amphetamines↗
PubMed1999

Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex: augmentation via 5-HT1A receptor antagonism.

Venlafaxine is a novel serotonin/noradrenaline reuptake inhibitor (SNRI) which has been shown clinically to be an effective antidepressant (AD) with a faster onset of action than serotonin specific reuptake inhibitors (SSRI). Preclinically, venlafaxine has been shown to potently inhibit dorsal raphe neuronal (DRN) firing through a 5-HT1A mediated mechanism, in a similar manner to SSRIs. Here we demonstrate the acute neurochemical effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline (NA) from the rat frontal cortex using in vivo microdialysis. Administration of venlafaxine (3-50 mg/kg s.c.) resulted in a significant dose-dependent increase in extracellular NA, but produced no significant increase in 5-HT concentrations. Combination treatment with the selective 5-HT1A antagonist WAY100635 produced a dose-dependent augmentation of venlafaxine-induced (3-30 mg/kg s.c) extracellular 5-HT concentrations, but had no further effect on NA above that produced by venlafaxine alone. WAY100635, at doses as low as 0.03 mg/kg s.c., maintained this potentiation effect. The beta-adrenergic/5-HT1A receptor antagonist (+/-)pindolol and the selective 5-HT1B/D antagonist GR127935 produced no significant augmentation of venlafaxine-induced changes in either 5-HT or NA. Using the alpha1 and alpha2-adrenoceptor antagonists, prazosin and idazoxane, we also demonstrate the role of the alpha-adrenoceptors in the augmentation of venlafaxine-induced changes. The possible mechanisms underlying venlafaxines improved clinical AD action and the potential for further enhancement of this SNRIs clinical effects are discussed.

Adrenergic alpha-Antagonists↗
PubMed2001

Venlafaxine in the treatment of premenstrual dysphoric disorder.

OBJECTIVE: To evaluate the efficacy and safety of venlafaxine, a new-generation antidepressant that selectively inhibits serotonin and norepinephrine reuptake, in the treatment of premenstrual dysphoric disorder (PMDD). METHOD: We conducted a randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial. After three screening cycles, including a single-blind placebo cycle, 164 women were randomly assigned to double-blind treatment with venlafaxine (50-200 mg/day) or placebo for four menstrual cycles. Primary outcome measures were the total premenstrual symptom scores as assessed by a daily symptom report (DSR) and the Hamilton Rating Scale for Depression. RESULTS: Venlafaxine was significantly more effective than placebo in reducing PMDD symptoms as assessed by DSR scores (P <.001 for last observation carried forward and observed analyses). Sixty percent of venlafaxine versus 35% of placebo subjects improved >50% (P =.003). Forty-three percent of venlafaxine subjects versus 25% of placebo subjects experienced symptom remission, defined as reduction of DSR scores to the postmenstrual level (P =.034). Venlafaxine treatment was significantly better than placebo for all statistically derived DSR factors (mood, function, pain, and physical symptoms). Improvement was relatively swift, with approximately 80% symptom reduction in the first treatment cycle. Mean venlafaxine doses ranged from 50 mg/day in the first treatment cycle to 130 mg/day in the fourth treatment cycle. Adverse events such as nausea, insomnia, and dizziness were mild and transient. CONCLUSIONS: Venlafaxine is significantly more efficacious than placebo for PMDD treatment. Response to treatment can occur in the first treatment cycle, and venlafaxine is well tolerated. Further studies are needed to evaluate the potential of intermittent (luteal phase) dosing for this cyclic disorder and the efficacy of long-term maintenance treatment with venlafaxine.

Adult↗
PubMed2001

Eucalyptus camaldulensis: volatiles from immature flowers and high production of 1,8-cineole and beta-pinene by in vitro cultures.

Calli of Eucalyptus camaldulensis Dehn were induced, for the first time, from immature flowers and stamens and established in the presence of 2,4-D and BA, under dark and light conditions. Immature flowers, of the same type used for callus induction, were submitted to hydrodistillation while the induced calli were extracted with n-pentane. The constituents of the n-pentane extracts and of the hydrodistillate were identified by GC-MS. The main constituents of the hydrodistillate from immature flowers were 1,8-cineole (34.7%), beta-pinene (7.7%), and spathulenol (9.5%). The n-pentane extract from calli developed from stamens consisted only of alkanes, alkenes and alcohols, while that of calli developed from immature flowers consisted mainly of monoterpenes (92.08-96.56%). The main monoterpenes produced in these calli, cultured in darkness and under light conditions, were 1,8-cineole, 62.70 and 69.26% as well as beta-pinene, 27.09 and the 25.31%, respectively.

Bicyclic Monoterpenes↗
PubMed2003

Monoterpenoid accumulation in 1,8-cineole, terpinolene and terpinen-4-ol chemotypes of Melaleuca alternifolia seedlings.

Individual leaves of the three most common chemotypes of Melaleuca alternifolia were examined both quantitatively and qualitatively for volatile constituents from the emergence of the first true leaves, through to 6-week-old tenth leaf set material. The 1,8-cineole and terpinolene chemotypes were investigated and compared with the recently reported commercial terpinen-4-ol chemotype. The 1,8-cineole chemotype was found to accumulate 1,8-cineole and associated p-menthanes limonene, terpinen-4-ol and alpha-terpineol gradually with increasing leaf set number. As with the terpinen-4-ol variety, higher than expected concentrations of the pinenes and terpinolene were found only in the early leaf sets. The terpinolene variety showed two stages of terpinolene accumulation, the first at leaf sets 2-3 similar to the unexpected biosynthesis of terpinolene in the terpinen-4-ol chemotype and the second at leaf sets 8-9 which is characteristic of the terpinolene variety.

Cyclohexane Monoterpenes↗
PubMedDate not supplied

An open clinical trial of venlafaxine treatment of fibromyalgia.

Of 15 patients with fibromyalgia who were first evaluated for the presence of Axis I psychiatric diagnoses by use of the Structured Clinical Interview for DSM-IV, 11 completed an open 8-week trial with the novel antidepressant venlafaxine. Six (55%) of 11 completers experienced a > or = 50% reduction of fibromyalgia symptoms. The presence of lifetime psychiatric disorders, particularly depressive and anxiety disorders, predicted a positive response to venlafaxine. These findings suggest that it is important to assess for comorbid psychiatric disorders in patients with fibromyalgia and that venlafaxine may be helpful to some of these patients.

Adolescent↗
PubMed2000

Cannabinoid and dopamine interaction in rodent brain: effects on locomotor activity.

We investigated interactions between cannabinoid and dopamine receptor systems in ICR mice. Mice were treated with the cannabinoid agonist levonantradol, the D(1) dopamine agonist 6-Br-APB, or the D(2) dopamine agonist quinelorane, or with combinations of these drugs. In addition, the D(1) antagonist SCH23390 was administered both alone and in combination with levonantradol. Two tests were used to evaluate changes in motor function: the immobility (ring stand) test and the catalepsy (bar) test. Levonantradol increased immobility and catalepsy in a dose-dependant manner. Both the D(2) agonist quinelorane and the D(1) agonist 6-Br-APB were able to attenuate the motor dysfunction caused by levonantradol. Administration of the D(1) antagonist SCH23390 enhanced the effects of levonantradol, producing a leftward shift of the log dose-response curve. These results differ from the augmentation by D(2) agonists of the hypoactivity induced by levonantradol in non-human primates [Meschler JP, Clarkson FA, Mathew PJ, Howlett AC, Madras BK. D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates. J Pharmacol Exp Ther 2000;292:952-959], suggesting that conclusions about the interactions between the dopamine and cannabinoid receptor motor systems in rodents may not extend to primates.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMedDate not supplied

Cannabinoid-induced motor incoordination through the cerebellar CB(1) receptor in mice.

Cannabinoids are known to impair motor function in humans and laboratory animals. We have observed dose-dependent motor incoordination in mice evaluated by rotorod following direct intracerebellar (i.c.b.) microinjection of synthetic cannabinoid agonists CP55,940 (5-25 microg) and HU-210 (1.56-6.25 microg), through permanently implanted stainless steel guide cannulas. The motor incoordination was marked at 15, 35 and 55 min post-microinjection. The motor incoordination elicited by HU-210 (6.25 microg) and CP55,940 (20 microg) was significantly blocked by the CB(1) receptor-selective antagonist SR141716A (25 microg i.c.b.), indicating mediation by a cerebellar CB(1) receptor. Further direct evidence of CB(1) mediation was obtained through a CB(1) receptor antisense/mismatch oligodeoxynucleotide approach (3 microg/12 h; total of six doses). Mice treated with intracerebellar antisense had a significantly diminished motor incoordination response to intracerebellar CP55,940 15 microg compared to mice that received intracerebellar mismatch or no prior treatment. Also, the response to intracerebellar CP55,940 in the CB(1) mismatch-treated mice did not differ from the mice that received only CP55,940. A separate study using a cerebellar tissue punching technique, following intracerebellar [3H]-CP55,940 microinjection, confirmed that cannabinoid drug dispersion following microinjections was exclusively confined to the cerebellum. Microinjection of CP55,940 (20 microg) into the hippocampus, an area with a large density of CB(1) receptors, did not impair motor coordination. Taken together, these results indicate that cannabinoid-induced motor impairment occurs by activation of a CB(1) receptor in the cerebellum. The participation of other brain motor areas in cannabinoid-induced motor incoordination will require future study.

Animals↗
PubMed2001

Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters.

The aim of the present study was to examine the effects of the cannabinoid agonist CP 55,940 and the antagonist SR 141716A, alone and in combination, on rat exploratory and anxiety-like behaviour in the holeboard and elevated plus-maze tests. A further aim was to evaluate the effects of these treatments on hypothalamic neurotransmitters. Animals treated with CP 55,940 doses of 0.125 and 0.1 mg/kg exhibited less exploration and an increase in anxiety-like behaviour accompanied by great motor inhibition. No hypoactivity was seen at 0.075 mg/kg dosage, but anxiety and neophobic responses persisted, indicating independent and specific effects. Motor activity effects induced by CP 55,940 were reversed by pretreatment with SR 141716A (3 mg/kg). Surprisingly, when administered on its own, the antagonist also induced a reduction in exploratory parameters and an increase in anxiety-like responses. These apparently similar effects might be caused by different neural mechanisms. Finally, CP 55,940 increased hypothalamic dopamine and serotonin levels. These increases might be involved in the activation of the hypothalamic-pituitary-adrenal axis described for cannabinoids.

Analgesics↗
PubMed2002

Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents.

This study characterized the influence of acute administration of diverse classes of antidepressant agent upon the spontaneous locomotor activity (LA) of mice in a novel, open-field environment. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, fluvoxamine, litoxetine and zimelidine, dose-dependently enhanced LA. Their actions were mimicked by the mixed 5-HT/noradrenaline (NA) reuptake inhibitors (SNRIs), venlafaxine, duloxetine and S33005. In contrast, clomipramine only slightly elevated LA and two further tricyclics, imipramine and amitriptyline, were inactive. Further, the selective NA vs. 5-HT reuptake inhibitors (NARIs), reboxetine, desipramine, maprotiline, nisoxetine and nortriptyline all failed to increase LA. The "atypical antidepressants," mianserin and mirtazapine, neither of which modify 5-HT reuptake, as well as the mixed SSRI/5-HT(2) antagonists, nefazodone and trazodone, also failed to increase LA. Doses of SSRI and SNRI which increased LA did not modify motor performance in the rotarod test. Further, they did not enhance LA in rats, suggesting that this response is characteristic of mice. Finally, upon prehabituation of mice to the activity chamber, the SSRI, citalopram, and the SNRI, venlafaxine, failed to increase LA. In conclusion, in mice exposed to a novel environment, inhibition of 5-HT reuptake by SSRIs and SNRIs enhances spontaneous LA in the absence of a generalized influence upon motor function. This response provides a simple parameter for characterization of SSRIs and SNRIs, and differentiates them from other classes of antidepressant agent. Although an influence upon arousal and/or anxiety is likely related to the increase in LA, the functional significance of this response requires additional elucidation.

Adrenergic Uptake Inhibitors↗
PubMed2002

SR-141716A-induced stimulation of locomotor activity. A structure-activity relationship study.

The central cannabinoid receptor (CB(1)) antagonist, SR-141716A, has been used extensively to ascertain that cannabinoids interact with the CB(1) receptor. SR-141716A has been shown to produce effects opposite of cannabinoids when administered alone. It has been theorized that SR-141716A may act as an inverse agonist at the CB(1) receptor or by disinhibiting an endogenous cannabinoid tone. In an effort to ascertain the exact interaction between SR-141716A and the CB(1) receptor, we have conducted a structure-activity relationship study to compare CB(1) receptor affinity of SR-141716A analogs with their ability to produce an increase in locomotor activity. SR-141716A produced a significant increase in locomotor activity in mice within the first hour of administration. Twenty SR-141716A analogs from five different chemical series were also tested. Our data implicate particular regions of the SR-141716A molecule that may be involved in stimulation and depression of locomotor activity. When the K(I) of the analogs was plotted against the percent stimulation that each analog produced, it is evident that there is no correlation between the ability of the analogs to stimulate locomotor activity and their affinity for the CB(1) receptor. [35S]GTPgammaS binding data indicate that SR-141716A and five of the analogs are inverse agonists. However, none of the analogs demonstrating inverse agonism produce stimulation of locomotor activity. It is therefore concluded that the SR-141716A-induced stimulation in locomotor activity is not the result of inverse agonist activity at the CB(1) receptor or by disinhibition of an endogenous tone.

Animals↗