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assessment of rimonabant like adverse effects of purported cb1r neutral antagonist cb2r agonist aminoalkylindole derivatives in mice

Abstract Background Cannabinoids may be useful in the treatment of CNS disorders including drug abuse and addiction, where both CB1R antagonists / inverse agonists and CB2R agonists have shown preclinical efficacy. TV-5-249 and TV-6-41, two novel aminoalkylindoles with dual action as neutral CB1R antagonists and CB2R agonists, previously attenuated abuse-related effects of ethanol in mice. Purpose To further characterize these drugs, TV-5-249 and TV-6-41 were compared with the CB1R antagonist / inverse agonist rimonabant in assays relevant to adverse effects and cannabinoid withdrawal. Procedures and findings The cannabinoid tetrad confirmed that TV-5-249 and TV-6-41 were devoid of CB1R agonist effects at behaviorally-relevant doses, and neither of the novel drugs induced rimonabant-like scratching. Generalized aversive effects were assessed, and rimonabant and TV-5-249 induced taste aversion, but TV-6-41 did not. Schedule-controlled responding and observation of somatic signs were used to assess withdrawal-like effects precipitated by rimonabant or TV-6-41 in mice previously treated with the high-efficacy CB1R agonist JWH-018 or vehicle. Rimonabant and TV-6-41 dose-dependently suppressed response rates in all subjects, but TV-6-41 did so more potently in JWH-018-treated mice than in vehicle-treated mice, while rimonabant equally suppressed responding in both groups. Importantly, rimonabant elicited dramatic withdrawal signs, but TV-6-41 did not. Conclusions These findings suggest differences in both direct adverse effects and withdrawal-related effects elicited by rimonabant, TV-5-249, and TV-6-41, which could relate to neutral CB1R antagonism, CB2R agonism, or a combination of both. Both mechanisms should be explored and exploited in future drug design efforts to develop pharmacotherapies for drug dependence.

Assessment of rimonabant-like adverse effects of purported CB1R neutral antagonist / CB2R agonist aminoalkylindole derivatives in mice.

Abstract Background Cannabinoids may be useful in the treatment of CNS disorders including drug abuse and addiction, where both CB1R antagonists / inverse agonists and CB2R agonists have shown preclinical efficacy. TV-5-249 and TV-6-41, two novel aminoalkylindoles with dual action as neutral CB1R antagonists and CB2R agonists, previously attenuated abuse-related effects of ethanol in mice. Purpose To further characterize these drugs, TV-5-249 and TV-6-41 were compared with the CB1R antagonist / inverse agonist rimonabant in assays relevant to adverse effects and cannabinoid withdrawal. Procedures and findings The cannabinoid tetrad confirmed that TV-5-249 and TV-6-41 were devoid of CB1R agonist effects at behaviorally-relevant doses, and neither of the novel drugs induced rimonabant-like scratching. Generalized aversive effects were assessed, and rimonabant and TV-5-249 induced taste aversion, but TV-6-41 did not. Schedule-controlled responding and observation of somatic signs were used to assess withdrawal-like effects precipitated by rimonabant or TV-6-41 in mice previously treated with the high-efficacy CB1R agonist JWH-018 or vehicle. Rimonabant and TV-6-41 dose-dependently suppressed response rates in all subjects, but TV-6-41 did so more potently in JWH-018-treated mice than in vehicle-treated mice, while rimonabant equally suppressed responding in both groups. Importantly, rimonabant elicited dramatic withdrawal signs, but TV-6-41 did not. Conclusions These findings suggest differences in both direct adverse effects and withdrawal-related effects elicited by rimonabant, TV-5-249, and TV-6-41, which could relate to neutral CB1R antagonism, CB2R agonism, or a combination of both. Both mechanisms should be explored and exploited in future drug design efforts to develop pharmacotherapies for drug dependence.

Unexpected partial H_1-receptor agonism of imidazole-type histamine H_3-receptor antagonists lacking a basic side chain

Objective and design: The putative partial H_1-receptor agonism of some H_3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. Methods: Whole segments of guinea-pig ileum were mounted in Tyrode’s solution under isotonic conditions in the presence of atropine (10^-7 M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H_1-receptor agonists were added cumulatively to determine agonist potency (pEC_50) and intrinsic activity (E_max) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H_1-receptor antagonists were incubated for 3–15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H_1 receptor (pK_P or pA_2 value, respectively). Results: Several analogues of FUB 372 displayed low H_1-receptor affinities (pA_2 or pKP 4.2–5.5) except for a methyl benzoate derivative (pA_2 = 6.81, Schild plot slope unity). FUB 372, four ortho -substituted derivatives (R = F, CH_3, OCH_3, CF_3), and ciproxifan were weak contractile agents ( E _max 9–38%, pEC_50 4.73–5.68, histamine: 6.70) susceptible to antagonism by the H_1-antihistaminergic drug mepyramine (2·10^-9–10^-7 M). Agonist potency and H_1-receptor affinity of these compounds did not correlate with the data of a set of H_1-histaminergic 2-phenylhistamines bearing the same substituents. Conclusions: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H_1-receptor agonists lacking a basic side chain.

Unexpected partial H_1-receptor agonism of imidazole-type histamine H_3-receptor antagonists lacking a basic side chain

Objective and design: The putative partial H_1-receptor agonism of some H_3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. Methods: Whole segments of guinea-pig ileum were mounted in Tyrode’s solution under isotonic conditions in the presence of atropine (10^-7 M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H_1-receptor agonists were added cumulatively to determine agonist potency (pEC_50) and intrinsic activity (E_max) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H_1-receptor antagonists were incubated for 3–15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H_1 receptor (pK_P or pA_2 value, respectively). Results: Several analogues of FUB 372 displayed low H_1-receptor affinities (pA_2 or pKP 4.2–5.5) except for a methyl benzoate derivative (pA_2 = 6.81, Schild plot slope unity). FUB 372, four ortho -substituted derivatives (R = F, CH_3, OCH_3, CF_3), and ciproxifan were weak contractile agents ( E _max 9–38%, pEC_50 4.73–5.68, histamine: 6.70) susceptible to antagonism by the H_1-antihistaminergic drug mepyramine (2·10^-9–10^-7 M). Agonist potency and H_1-receptor affinity of these compounds did not correlate with the data of a set of H_1-histaminergic 2-phenylhistamines bearing the same substituents. Conclusions: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H_1-receptor agonists lacking a basic side chain.

Heterogeneity of thromboxane A2 (TP‐) receptors: evidence from antagonist but not agonist potency measurements

1
Thromboxane A2 (TP-) receptors in human, rat and rabbit platelets and in smooth muscle of guinea-pig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure.

2
On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA2 > 9,11-azo PGH2 > 9,11-endoxy-10a-homo PGH2 > U-46619 (standard) > PGH2 = 16-p-fluorophenoxy-ω-tetranor PGF2α > 16,16-dimethyl PGF2α. Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA2, at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP-receptor.

3
Five prostanoids, EP 109, EP 167, EP 204, PTA2 and 16,20-methano PTA2, exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration-response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20-methano PTA2 could be treated as a pure antagonist.

4
With U-46619 as agonist, the pA2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20-methano PTA2 > BM 13177. There was a similar trend on rabbit platelets but pA2 values were 1.0–1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets.

5
None of the antagonists was highly potent on the rabbit aorta (pA2 values 0.05).

6
The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP-receptor subtypes and further suggests that the agonist recognition sites of the TP-receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP-receptors. However, classification into TP1-, TP2-receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.

heterogeneity of thromboxane a2 tp receptors evidence from antagonist but not agonist potency measurements

1
Thromboxane A2 (TP-) receptors in human, rat and rabbit platelets and in smooth muscle of guinea-pig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure.

2
On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA2 > 9,11-azo PGH2 > 9,11-endoxy-10a-homo PGH2 > U-46619 (standard) > PGH2 = 16-p-fluorophenoxy-ω-tetranor PGF2α > 16,16-dimethyl PGF2α. Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA2, at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP-receptor.

3
Five prostanoids, EP 109, EP 167, EP 204, PTA2 and 16,20-methano PTA2, exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration-response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20-methano PTA2 could be treated as a pure antagonist.

4
With U-46619 as agonist, the pA2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20-methano PTA2 > BM 13177. There was a similar trend on rabbit platelets but pA2 values were 1.0–1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets.

5
None of the antagonists was highly potent on the rabbit aorta (pA2 values 0.05).

6
The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP-receptor subtypes and further suggests that the agonist recognition sites of the TP-receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP-receptors. However, classification into TP1-, TP2-receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.