(.+-.)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole: a conformationally restricted analog of 5-carboxamidotryptamine with selectivity for the serotonin 5-HT1D receptor

King, Frank D.; Brown, Anthony M.; Gaster, Laramie M.; Kaumann, Alberto J.; Medhurst, Andrew D.; Parsons, Andrew A.; Patch, T.L.; Raval, Pravin

doi:10.1021/jm00065a015

Cited by 35 publications

(18 citation statements)

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“…BRL 56905 is more potent than sumatriptan at postjunctional ca-5-HT 1D/1B receptors in dog saphenous vein (King et al 1993) whilst SKF 99101H, but not sumatriptan, induced hypothermia in guinea-pigs, possibly reflecting the superior brain penetrancy of SKF 99101H. In the present study, given the limitations of the measurement of pIC 50 values, there was little difference in the potency of BRL 56905 and sumatriptan, given that the former value is a pIC 40 and the latter a pIC 45 value.…”

Section: Discussionmentioning

confidence: 89%

“…In addition, we have shown that BRL 56905 and SKF 99101H, which do not discriminate between h-5-HT 1D and h-5-HT 1B receptors (Table 1), and induce postjunctional ca-5-HT 1D/1B receptor-mediated contraction in dog saphenous vein (King et al 1993) and postjunctional 5-HT 1D/1B receptor-mediated hypothermia in the guinea-pig (Hatcher et al 1995) respectively, also activate prejunctional ca-5-HT 1D/1B receptors in dog saphenous vein, resulting in the inhibition of neurotransmitter release and neurogenic contraction. The potency estimate for SKF 99101H-induced inhibition of electrically-evoked [ 3 H]noradrenaline release in dog saphenous vein (Table 1) is consistent with the potency of SKF 99101H-induced inhibition of electricallyevoked [ 3 H]5-HT release observed in guinea-pig cerebral cortex slices (pIC 50 = 6.8; personal communication, Dr. C. Roberts), a preparation recently shown to involve 5-HT 1B receptors (Bühlen et al 1996).…”

Section: Discussionmentioning

confidence: 96%

“…For example, BRL 56905 has low affinity for 5-HT 1A , 5-HT 1C and 5-HT 2 receptors (King et al 1993), whilst SKF 99101H has low affinity for 5-HT 1E , 5-HT 2 and 5-HT 3 receptors (Hatcher et al 1995). In addition, there is no evidence for the existence of 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 or 5-HT 7 receptors in dog saphenous vein, and an effect on 5-HT 1A and 5-HT 2 receptors, at least of 5-HT, has been previously discounted (Paiva et al 1988).…”

Section: Discussionmentioning

confidence: 99%

“…Binding studies have shown that BRL 56905 (King et al 1993) and SKF 99101H (Hatcher et al 1995) have high affinity and selectivity for 5-HT 1D and 5-HT 1B receptors, but do not discriminate between these two subtypes (Table 1). Functional studies suggest that both agonists activate postjunctional 5-HT 1D/1B receptors.…”

Section: Introductionmentioning

confidence: 99%

“…Functional studies suggest that both agonists activate postjunctional 5-HT 1D/1B receptors. For example, BRL 56905 induces postjunctional 5-HT 1D/1B receptormediated contraction in dog saphenous vein and rabbit basilar artery (King et al 1993), whilst SKF 99101H induces 5-HT 1D/1B receptor-mediated hypothermia in the guinea-pig (Hatcher et al 1995). However, until now, there are no reports on the prejunctional inhibitory activity of these compounds.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous measurement of [3H]noradrenaline release and neurogenic contraction under identical conditions, to determine the prejunctional inhibitory effects of SKF 99101H and BRL 56905 in dog saphenous vein

Medhurst

Brown

Kaumann

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Using a tissue bath system which allowed the simultaneous measurement of electrically-induced [3H]noradrenaline release and neurogenic contraction under identical conditions, we investigated the prejunctional inhibitory activity of the selective 5-HT(1D/1B) receptor agonists BRL 56905 ((+/-)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole) and SKF 99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate), compared to sumatriptan and 5-HT. Transmural electrical stimulation (2 Hz) of dog saphenous vein induced consistent increases in [3H]noradrenaline release as well as reproducible contractile responses (<10% decrease over four stimulation periods). BRL 56905, SKF 99101H, sumatriptan and 5-HT (60 nM-6 microM) inhibited electrically-evoked [3H]noradrenaline release and neurogenic contractile responses in dog saphenous vein. However, despite being measured under identical conditions, the inhibition of [3H]noradrenaline release was consistently greater than the inhibition of neurogenic contraction induced by a particular concentration of agonist, suggesting that neurogenic contractile responses in dog saphenous vein result from the combined release of noradrenaline and other non-noradrenergic neurotransmitters. Under the present assay conditions, since the agonists produced only small (BRL 56905, sumatriptan and 5-HT) or marginal (SKF 99101H) contractile responses, it is unlikely that this is the cause of the discrepancy observed between inhibition of release and inhibition of contraction. The inhibitory effects of BRL 56905, sumatriptan and 5-HT were blocked by the 5-HT(1D/1B) receptor antagonist methiothepin, consistent with the involvement of canine ca-5-HT(1D/1B) receptors in inhibiting neurotransmitter release and subsequent smooth muscle contraction in dog saphenous vein. The present results show that the novel 5-HT(1D/1B) receptor agonists BRL 56905 and SKF 99101H are at least as potent as sumatriptan and 5-HT, at activating prejunctional inhibitory ca-5-HT(1D/1B) heteroreceptors on sympathetic axon terminals in dog saphenous vein. In addition, when measured simultaneously in the same tissue preparation, [3H]noradrenaline release was inhibited to a much greater extent than neurogenic contraction by any particular agonist.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Simultaneous measurement of [3H]noradrenaline release and neurogenic contraction under identical conditions, to determine the prejunctional inhibitory effects of SKF 99101H and BRL 56905 in dog saphenous vein

Medhurst

Brown

Kaumann

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Analog Design

Cannon

2003

Burger's Medicinal Chemistry and Drug Discovery

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The chapter addresses the design of nonprotein, nonpeptide drug analogs. Strategies and applications of classical and nonclassical bioisosteres, rigid and semirigid analogs; homologation of alkyl chains; changes in ring size and ring‐position isomers; substitution of aromatic for aliphatic rings; alteration of stereochemistry; design of fragments of lead molecules; and variation of interatomic distances are discussed. Numerous examples from the literature of each type of molecular modification are presented, together with summaries of pharmacological consequences of the modifications. Advantages and disadvantages of each category are cited.

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meta‐C−H Arylation and Alkylation of Benzylsulfonamide Enabled by a Palladium(II)/Isoquinoline Catalyst

Cheng

Wang

2017

Angewandte Chemie

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Palladium(II)-catalyzed meta-C À Ha rylation and alkylation of benzylsulfonamide using 2-carbomethoxynorbornene (NBE-CO 2 Me) as atransient mediator are realized by using anewly developed electron-deficient directing group and isoquinoline as aligand. This protocol features broad substrate scope and excellent functional-group tolerance.T he metasubstituted benyzlsulfonamides can be readily transformed into sodium sulfonates,s ulfonate esters,a nd sulfonamides,a s well as styrenes by Julia-type olefination. The unique impact of the isoquinoline ligand underscores the importance of subtle matching between ligands and the directing groups. Angewandte ChemieCommunications 8185

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(.+-.)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole: a conformationally restricted analog of 5-carboxamidotryptamine with selectivity for the serotonin 5-HT1D receptor

Cited by 35 publications

References 2 publications

Simultaneous measurement of [3H]noradrenaline release and neurogenic contraction under identical conditions, to determine the prejunctional inhibitory effects of SKF 99101H and BRL 56905 in dog saphenous vein

Simultaneous measurement of [3H]noradrenaline release and neurogenic contraction under identical conditions, to determine the prejunctional inhibitory effects of SKF 99101H and BRL 56905 in dog saphenous vein

Analog Design

meta‐C−H Arylation and Alkylation of Benzylsulfonamide Enabled by a Palladium(II)/Isoquinoline Catalyst

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