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AM-1346 - a synthetic cannabinoid

Overview

AM1346 is a cannabinoid receptor type 1 (CB1R) anandamide analog [alkoxyacid amide of N-eicosa-(5Z, 8Z, 11Z, 14Z)-tetraenylamine] with high affinity and selectivity for the CB1 vs. CB2 receptor [Ki (CB1)=1.5 nmol/l; Ki (CB2)=152 nmol/l]. The present study characterized the effects of AM1346 (5.6–18 mg/kg) and its interaction with the CB1R antagonist/inverse agonist SR141716 (1–5.6 mg/kg) on open-field behaviors of rats. AM1346 reduced ambulation (horizontal activity), rearing (vertical activity) and increased the degree of circling and the latency to leave the central area of the open-field arena.
 
AM1346 also tended to reduce defecation and to increase vocalization in a dose-dependent manner. In pretreatment studies, SR141716 completely blocked the effects of AM1346 on circling and latency and partially antagonized the effects of 18 mg/kg AM1346 on ambulation and rearing. SR141716 also tended to decrease AM1346-induced vocalization in a dose-dependent manner. Earlier studies have shown that SR141716, given alone, can increase grooming behavior and, as well, produces dose-related increases in scratching. In the present studies, these effects were attenuated in a dose-related manner by AM1346. The present profile of behavioral effects for AM1346 is consistent with its designation as a CB1R agonist. When combined with drug discrimination data (surmountable antagonism of effects of SR141716 by Δ9-THC and AM1346 but not by methanandamide, i.e. AM356), these data indicate that the anandamide analog AM1346 may be more behaviorally similar to cannabinoids like Δ9-THC than to other anandamide-based molecules such as methanandamide.

Science & Research

Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Delta9-THC or (R)-methanandamide (AM-356).

Psychopharmacology (Berl). 2006 Oct;188(3):315-23. Epub 2006 Sep 5.

Source

Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA, 19122, USA.

Abstract

OBJECTIVE:

To characterize in vivo the high-affinity cannabinoid CB1 receptor (CB1R) selective anandamide analog AM-1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination procedures. D-amphetamine and also morphine in the (R)-methanandamide-trained group (see below) were examined to assess pharmacological specificity.

METHODS:

Three groups of rats were trained to discriminate between vehicle and (1) 1.8 mg/kg Delta9-tetrahydrocannabinol (Delta9-THC); (2) 5.6 mg/kg Delta9-THC; and (3) 10 mg/kg (R)-methanandamide (AM-356; a metabolically stable analog of anandamide). Delta9-THC was given i.p. 30 min and (R)-methanandamide 15 min before training.

RESULTS:

AM-1346 generalized to all three training conditions, both at 15 and 30 min after administration. The rank order potency was: Delta9-THC > AM-1346 > (R)-methanandamide. AM-1346 appeared slightly more potent 30 min compared to 15 min postadministration.

In the presence of 0.3 mg/kg of the CB1R antagonist/inverse agonist SR-141716A, the dose generalization curves of Delta9-THC and AM-1346 resulted in parallel shifts to the right in the 1.8 mg/kg Delta9-THC-trained group. A long duration of action for AM-1346 (relative to AM-356) was indicated in tests where AM-1346 was examined in the 5.6 mg/kg Delta9-THC-trained group. Neither D-amphetamine, nor morphine generalized in either of the groups, suggesting pharmacological specificity.

CONCLUSION:

Unlike (R)-methanandamide, the surmountable antagonism between SR-141716A and AM-1346 shows that the structural features of anandamide can be modified in ways that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB1R agonists derived from an anandamide template.

PMID:
16953384
[PubMed - indexed for MEDLINE]
 
 

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Synthetic Cannabinoid May Aid Fertility In Smokers

Article Date: 05 Dec 2006 - 15:00 PDT

 A reproductive medicine specialist at the University at Buffalo has shown that a new compound may improve the fertility of tobacco smokers who have low sperm count and low percentage sperm motility.

The sperm from male smokers were washed with a synthetic chemical called AM-1346. After incubation, there was a doubling in the fertilizing capacity of sperm from poor quality semen, results showed.

Lani Burkman, Ph.D., and colleagues presented the findings at the 2006 meeting of the American Society of Reproductive Medicine held recently in New Orleans. "Based on our previous data and published literature, it is clear that most tobacco smokers will exhibit a small or a significant decline in fertility," she stated. "Nicotine addiction is quite powerful. The best solution is to stop smoking and then wean yourself off of all nicotine products. But for smokers who can't quit, the in vitro use of AM-1346 may significantly improve their fertilizing capacity."

Burkman, associate professor in the departments of gynecology/obstetrics and urology and head of the Section on Andrology in the UB School of Medicine and Biomedical Sciences, previously demonstrated that sperm functions critical for fertilization are altered by nicotine exposure, whether in vitro, or through long-term tobacco use. Two-thirds of the male smokers studied had decreased fertility; some showed a serious loss.

The new study involved nine selected smokers (22 experiments) who had been evaluated previously for sperm fertilizing potential using the outside cover of a human egg, called the zona pellucida. Four men had a high number of sperm attaching to the zona (normal, Group I), while five other smokers had sperm with poor egg binding (poor fertilizing potential, Group II).

The new experiments were designed to evaluate whether sperm with poor fertilizing capacity from smokers could be treated so that egg binding was improved. Specifically, the researchers studied a potential interaction between two chemical systems that control sperm.

"Human sperm carry the cholinergic receptor, which responds to the neurotransmitter acetylcholine," noted Burkman. "Nicotine mimics acetylcholine and binds to the cholinergic receptor." In earlier research, Burkman and colleagues also showed that human sperm contain cannabinoid receptors, which respond to marijuana, as well as natural cannabinoids occurring in the body.

"Research from other scientists indicates that the cholinergic system and the cannabinoid system naturally regulate human sperm and help prepare them for fertilizing an egg," she said. "Our research suggests that this natural regulation is out of balance for the majority of smokers when sperm are continuously exposed to nicotine.

"We think there is an important communication between the cannabinoid and cholinergic receptor systems in human sperm," said Burkman. "No one has shown this interaction before when looking at human tissue. AM-1346, the drug that we tested, is a synthetic version of a natural cannabinoid found in the body.

"In 22 Hemizona tests, we showed that the response to AM-1346 depended on the initial fertility of the tobacco smoker, and if his semen showed poor quality, meaning low sperm count and low percentage motility."

The sperm from Group II volunteers were incubated with AM-1346 for several hours and then retested in the Hemizona Assay. Six experiments in Group II started with semen of low quality and all six resulted in stimulation of sperm binding to the zona ranging from 133 percent to 330 percent, with a mean of 201 percent, when compared to their own untreated sperm, results showed.

"In contrast," said Burkman, "samples from Group I (normal fertility, normal semen quality) reacted in the opposite manner. This two-way, or biphasic, response is common for cannabinoid action. With Group I, the drug AM-1346 caused a substantial decrease in sperm binding to the zona for eight out of nine samples.

"This opposite response must be studied further," Burkman said. "It might be tied to early-versus-late steps in fertilization, where it is expected that one process is slowed down while another process is stimulated.

"It does appear that sperm functioning in tobacco smokers with low fertility and low semen quality is quite different when compared to smokers with higher fertility and good semen quality. Nicotine appears to change the sperm membranes and sperm receptors. It also raises the question of why sperm from some smokers are protected from the effects of tobacco and nicotine."

Roxanne Mroz and MaryLou Bodziak, UB research associates, contributed to this work, along with UB undergraduate students Stuti Tambar and Brian Telesz. Alexandros Makriyannis, Ph.D., from Northeastern University, created AM-1346.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center.

Contact: Lois Baker
University at Buffalo

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