Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB sub(1) and CB sub(2) receptors were determined. In the 2-phenyl series (5) the ...N-alkyl group was varied from n-propyl to n-heptyl. A second series of 23 1-pentyl-2-aryl-4-(1- naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB sub(1) receptor affinities in the 6-30 nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R = C sub(5)H sub(11)) support the hypothesis that these pyrroles interact with the CB sub(1) receptor primarily by aromatic stacking.
Background & Aims Chronic stress is associated with visceral hyperalgesia in functional gastrointestinal disorders. We investigated whether corticosterone plays a role in chronic psychological ...stress-induced visceral hyperalgesia. Methods Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous corticosterone injection daily for 10 consecutive days in the presence or absence of corticoid-receptor antagonist RU-486 and cannabinoid-receptor agonist WIN55,212-2. The visceromotor response to colorectal distension was measured. Receptor protein levels were measured and whole-cell patch-clamp recordings were used to assess transient receptor potential vanilloid type 1 (TRPV1) currents in L6–S2 dorsal root ganglion (DRG) neurons. Mass spectrometry was used to measure endocannabinoid anandamide content. Results Chronic WA stress was associated with visceral hyperalgesia in response to colorectal distension, increased stool output and reciprocal changes in cannabinoid receptor 1 (CB1) (decreased) and TRPV1 (increased) receptor expression and function. Treatment of WA stressed rats with RU-486 prevented these changes. Control rats treated with serial injections of corticosterone in situ showed a significant increase in serum corticosterone associated with visceral hyperalgesia, enhanced anandamide content, increased TRPV1, and decreased CB1 receptor protein levels, which were prevented by co-treatment with RU-486. Exposure of isolated control L6-S2 DRGs in vitro to corticosterone reproduced the changes in CB1 and TRPV1 receptors observed in situ, which was prevented by co-treatment with RU-486 or WIN55,212-2. Conclusions These results support a novel role for corticosterone to modulate CB1 and TRPV1-receptor pathways in L6-S2 DRGs in the chronic WA stressed rat, which contributes to visceral hyperalgesia observed in this model.
Fourteen novel CB sub(2) receptor selective cannabinoids were synthesized via initial Lewis acid catalyzed rearrangement of resorcinol precursors to obtain the cannabinoid moiety. These are the ...1-methoxy-9-hydroxyhexahydrocannabinols and the 1-deoxy-9-hydroxyhexahydrocannabinols, with 1',1'-dimethylalkyl side chains of four to seven carbon atoms at C-3 of the cannabinoid nucleus. The cannabinols synthesized and described in this paper all exhibit greater affinity for the CB sub(2) receptor than for the CB sub(1) receptor. Exceptionally high CB sub(2) affinity was observed for 1-deoxy-9 beta -hydroxy- dimethylhexylhexahydrocannabinol (JWH-361, 9, n = 3) K sub(i) = 2.7 nM and 1-deoxy-9 beta -hydroxydimethylpentylhexahydrocannabinol (JWH-300, 9, n = 2) K sub(i) = 5.3 nM. In general, the stereochemistry of the 9-hydroxy group is important and the beta -orientation enhances both CB sub(2) receptor affinity and selectivity.
The synthesis and pharmacology of two series of 11-nor-9-hydroxy-HHCs are described. R
=
H, OCH
3; R′
=
n-propyl to
n-hexyl.
Fourteen novel CB
2 receptor selective cannabinoids were synthesized via ...initial Lewis acid catalyzed rearrangement of resorcinol precursors to obtain the cannabinoid moiety. These are the 1-methoxy-9-hydroxyhexahydrocannabinols and the 1-deoxy-9-hydroxyhexahydrocannabinols, with 1′,1′-dimethylalkyl side chains of four to seven carbon atoms at C-3 of the cannabinoid nucleus. The cannabinols synthesized and described in this paper all exhibit greater affinity for the CB
2 receptor than for the CB
1 receptor. Exceptionally high CB
2 affinity was observed for 1-deoxy-9β-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361,
9,
n
=
3)
K
i
=
2.7
nM and 1-deoxy-9β-hydroxydimethylpentylhexahydrocannabinol (JWH-300,
9,
n
=
2)
K
i
=
5.3
nM. In general, the stereochemistry of the 9-hydroxy group is important and the β-orientation enhances both CB
2 receptor affinity and selectivity.
Three series of new cannabinoids were prepared and their affinities for the CB
1 and CB
2 cannabinoid recptors were determined. These are the 1-methoxy-3-(1′,1′-dimethylalkyl)-, ...1-deoxy-11-hydroxy-3-(1′,1′-dimethylalkyl)- and 11-hydroxy-1-methoxy-3-(1′,1′-dimethylalkyl)-Δ
8-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB
2 receptor than for the CB
1 receptor, however only 1-methoxy-3-(1′,1′-dimethylhexyl)-Δ
8-THC (JWH-229,
6e) has effectively no affinity for the CB
1 receptor (
K
i=3134±110
nM) and high affinity for CB
2 (
K
i=18±2
nM).
The synthesis and pharmacology of three series of CB
2 receptor ligands are described. R=H, OCH
3; R′=1,1-dimethylethyl to 1,1-dimethylheptyl; R″=CH
3, CH
2OH.
We study the effect of disc self-gravity on instabilities associated with gaps opened by a giant Saturn mass planet in a protoplanetary disc that lead to the formation of vortices. We also study the ...non-linear evolution of the vortices when this kind of instability occurs in a self-gravitating disc as well as the potential effect on type III planetary migration due to angular momentum exchange via co-orbital flows.
It is shown analytically and is confirmed through linear calculations that vortex-forming modes with low azimuthal mode number, m, are stabilized by the effect of self-gravity if the background structure is assumed fixed. However, the disc's self-gravity also affects the background gap surface density profile in a way that destabilizes modes with high m. Linear calculations show that the combined effect of self-gravity through its effect on the background structure and its direct effect on the linear modes shifts the most rapidly growing vortex mode to higher m.
Hydrodynamic simulations of gaps opened by a Saturn mass planet show more vortices develop with increasing disc mass and therefore importance of self-gravity. For sufficiently large disc mass the vortex instability is suppressed, consistent with analytical expectations. In this case a new global instability develops instead.
In the non-linear regime, we found that vortex merging is in general increasingly delayed as the disc mass increases and in some cases multiple vortices persist until the end of simulations. For massive discs in which the vortices merge, the post-merger vortex is localized in azimuth and has similar structure to a Kida-like vortex. This is unlike the case without self-gravity where vortices merge to form a larger vortex extended in azimuth.
In order to study the properties of the vortex systems without the influence of the planet, we also performed a series of supplementary simulations of co-orbital Kida-like vortices. We found that self-gravity enables Kida-like vortices to execute horseshoe turns upon encountering each other. As a result, vortex merging is avoided on time-scales where it would occur without self-gravity. Thus we suggest that mutual repulsion of self-gravitating vortices in a rotating flow is responsible for the delayed vortex merging seen in the disc-planet simulations.
The effect of self-gravity on vortex-induced migration in low-viscosity discs is briefly discussed. We found that when self-gravity is included and the disc mass is in the range where vortex-forming instabilities occur, the vortex-induced type III migration of Lin & Papaloizou is delayed. There are also expected to be longer periods of slow migration between the short bursts of rapid migration compared to what occurs in a simulation without self-gravity. However, the extent of induced rapid migration is unchanged and involves flow of vortex material across the gap, independent of whether or not self-gravity is included.
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