Sulfonamides with the N-alkyl-N′-dialkylguanidine moiety as 5-HT7 receptor ligands (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2010
a b s t r a c t N 0 -Cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT 1A ligands as potential pharmacological tools in studies of wide spread psychiatric disorders. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4substituted piperazine) known to be critical in order to have affinity on 5-HT 1A receptor and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT 1A and moderate to no affinity for other relevant receptors (5-HT 2A , 5-HT 2C , D 1 , D 2 , a 1 and a 2 ).
Characterization of SB-269970-A, a selective 5-HT 7 receptor antagonist
British Journal of Pharmacology, 2000
1 The novel 5-HT 7 receptor antagonist, SB-269970-A, potently displaced [ 3 H]-5-CT from human 5-HT 7(a) (pK i 8.9+0.1) and 5-HT 7 receptors in guinea-pig cortex (pK i 8.3+0.2). 2 5-CT stimulated adenylyl cyclase activity in 5-HT 7(a) /HEK293 membranes (pEC 50 7.5+0.1) and SB-269970-A (0.03 ± 1 mM) inhibited the 5-CT concentration-response with no signi®cant alteration in the maximal response. The pA 2 (8.5+0.2) for SB-269970-A agreed well with the pK i determined from [ 3 H]-5-CT binding studies. 3 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC 50 of 8.4+0.2) was inhibited by SB-269970-A (0.3 mM) with a pK B (8.3+0.1) in good agreement with its antagonist potency at the human cloned 5-HT 7(a) receptor and its binding anity at guinea-pig cortical membranes. 4 5-HT 7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. 5 SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min 71 kg 71 ). Following a single dose (3 mg kg 71 ) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 6 5-CT (0.3 mg kg 71 i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED 50 2.96 mg kg 71 i.p.) and the non-selective 5-HT 7 receptor antagonist metergoline (0.3 ± 3 mg kg 71 s.c.), suggesting a role for 5-HT 7 receptor stimulation in 5-CT induced hypothermia in guinea-pigs. 7 SB-269970-A (30 mg kg 71 ) administered at the start of the sleep period, signi®cantly reduced time spent in Paradoxical Sleep (PS) during the ®rst 3 h of EEG recording in conscious rats.
European Journal of Pharmacology, 1997
Native brain 5-HT1B/1D) receptors were studied using the novel antagonist, [3H]GR 125,743 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyri dyl)benzamide). In guinea-pig striatal membranes, [3H]GR 125,743 displayed rapid association (t1/2 = 4.5 min), high (90%) specific binding and high affinity (K(d) = 0.29 nM), although B(max) values (fmol/mg protein) varied according to brain region-striatum: 199; frontal cortex: 89; hippocampus: 79; cerebellum: 26. In frontal cortex, the B(max) determined with [3H]5-CT ([3H]carboxamidotryptamine) was significantly higher (178; P < 0.05), suggesting that it also labels other binding sites. In striatal membranes, guanylylimidodiphosphate (GppNHp) inhibited [3H]5-CT but not [3H]GR 125,743 binding, suggesting that the latter has antagonist properties. Nevertheless, in competition binding experiments, the pK(i) values obtained with [3H]GR 125,743 and [3H]5-CT for 20 serotonergic ligands, including L 694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]-1H-indole-3-yl]ethylamine), GR46,611 (3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylami de), sumatriptan and alniditan, were highly correlated (r = 0.99). Ketanserin and ritanserin showed low affinity for [3H]GR 125,743 binding to guinea-pig striatal sites (K(i) = 12600 and 369 nM), suggesting that 5-HT1B (rather than 5-HT1D) receptors are predominantly labelled in this tissue. The present data indicate that [3H]GR 125,743 is a useful tool for studying native 5-HT1B/1D receptors.
Characterization of a novel and potent 5-hydroxytryptamine1A receptor antagonist
Pharmacology Biochemistry and Behavior, 1991
LIAU, L. M., A. J. SLEIGHT, J. PITHA AND S. J. PEROUTKA. Characterization of a novel and potent 5-hydroxytryptaminelA receptor antagonist. PHARMACOL BIOCHEM BEHAV 38(3) 555-559, 1991.--A series of pindolol derivatives (n=7) was analyzed in radioligand binding, biochemical and behavioral studies. Three of these drugs (Compounds A, B, and C) are extremely 3 potent (i.e., Ki values < 1.0 nM) at 5-hydroxytryptarninelA (5-HTIA) sites labeled by [ HI 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Moreover, these drugs are selective in that they are approximately an order of magnitude less potent at beta-adrenergic receptors labeled by 3H-dihydroalprenolol (DHA). Compound A (Nl-(bromoacetyl)-NS-[3-(4-indolyloxy)-2-hydroxypropyl] -(Z)-l,8-diamino-p-methane)
Pharmacology of a novel selective 5-hydroxytryptamine 1B receptor antagonist, AR-A000002
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
The terminal 5-HT 1B autoreceptors have attracted great pharmacological interest since they are potential targets for compounds modifying serotonergic neurotransmission. In the present work the in vivo biochemical properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel selective 5-HT 1B receptor antagonist, are reported.
N -Methyl-5- tert -butyltryptamine: A Novel, Highly Potent 5-HT 1D Receptor Agonist
Journal of Medicinal Chemistry, 1999
It has been observed that reported 5-HT1D receptor agonists have at least one heteroatom (N, O, or S) on the 5-substituent of the indole. This has led to the hypothesis that a 5-substituent capable of participating in hydrogen bonding is critical for conveying high affinity. This article describes the synthesis and biological evaluation of a new series of 5-alkyltryptamine analogues, which does not have a heteroatom in the 5-substituent group. In contrast to the hypothesis, 5-alkyltryptamines all exhibit high binding affinities for the human 5-HT1D receptor. The size of the lipophilic alkyl group at the 5-position of the indole has significant impact on the 5-HT1D binding affinity. Compounds with a tert-butyl group at the 5-position such as 9d, 10, and 11 were identified. These analogues display high binding affinity (Ki < 1 nM) and moderate receptor selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan, rizatriptan, and VML-251.