1,2,4]Triazole derivatives as 5-HT(1A) serotonin receptor ligands.

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.     

N-Propylnoraporphin-11-O-yl carboxylic esters as potent dopamine D(2) and serotonin 5-HT(1A) receptor dual ligands

A small series of N-propylnoraporphin-11-O-yl carboxylic esters with variant ester lengths were synthesized and their binding potencies at dopamine receptors (D(1), D(2)) and serotonin receptors (5-HT(1A), 5-HT(2A)) were evaluated. Monoesters 3a-f showed binding potency of 100 nM or less for the D(2) receptor, and potency of 10-30 nM for the 5-HT(1A) receptor. Butyryl ester 3d was found to be the best compound possessing the highest potency for both receptors, with K(i) values of 55 and 12 nM for D(2) and 5-HT(1A) receptors, respectively. There is no correlation between the binding potency and the length of the monoesters, but the diesters 9 and 10 were inactive for the D(2) receptor. The dual binding profile of these monoesters for the D(2) and 5-HT(1A) receptors may be useful for the treatment of neuropsychiatric disorders.     

Dopamine/serotonin receptor ligands. Part 15: Oxygenation of the benz-indolo-azecine LE 300 leads to novel subnanomolar dopamine D1/D5 antagonists

Relying on the high affinities of the benz-indolo-azecine LE 300 (1) and the hydroxylated dibenz-azecine LE 404 (2b) for the D1/D5 receptor subtypes, we synthesized methoxylated, hydroxylated and an indole-N methylated derivatives of 1 (Fig. 1). Hydroxylation of azecine derivatives is beneficial with regard to the affinities and selectivities for all the dopamine receptor subtypes. The 'serotonin-derived' 3-oxygenated target compounds but not the 11-oxygenated analogues were superior to the unsubstituted LE 300. 11-Methoxy-7,14-dimethyl-6,7,8,9,14,15-hexahydro-5H-indolo[3,2-f][3]benzazecine (3e) was found to be the most potent antagonist at D2/D3/D4 and D5 receptor subtypes (Ki for D5 = 0.23 nmol) of all known benz-indolo-azecines.     

2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands

2-(Anilino)imidazolines were identified as novel human 5-HT(1D) receptor ligands, but offered no particular advantage over previously reported 2-(benzyl)imidazolines. Pharmacokinetic and functional data were obtained for selected 2-(benzyl)imidazoline derivatives.     

1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands

4-Sulfonyl analogs of 1-(1-naphthyl)piperazine bind at human 5-HT6 receptors and represent a novel class of human 5-HT6 receptor ligands.     

The serotonin 5-HT1D receptor: A progress review

Most of the known neurotransmitters interact with more than one type of receptor. Some of them even dispose of receptor subtypes to exert their actions. Serotonin, far from being an exception to that, possesses at least 3 classes of receptors, which have all been reported to be heterogeneous, although convincing data only exist for the 5-HT₁ class. This name has been proposed in 1979, two years before the introduction of A and B in the nomenclature to account for the observed heterogeneity of these cites. The 5-HT_1C receptor subtype was first described in 1984 and the last member of the family, named 5-HT_1D, was characterized in 1987. The pharmacological profiles, the signal transducing systems and the anatomical localizations, both at the regional and cellular levels, of all these subtypes have been investigated and possible functions have been proposed for each of them. Moreover, last and most definitive demonstration of the subtype individuality, the gene or complementary DNA coding for the 5-HT_1A and 5-HT_1C (and 5-HT₂) receptors have been cloned and sequenced. Such data are still missing for 5-HT_1D (and 5-HT_1B) receptors, but will certainly be provided in the next few years. However and waiting for this decisive clue, the characterization of the 5-HT_1D subtype leaves no doubt concerning its significance as a functional 5-HT receptor. This review will concentrate on the characteristics of this subtype of 5-HT receptor.Abbreviations 5-CT 5-carboxamidotryptamine - 5-MeOT 5-methoxy-tryptamine - 5-MeODMT N,N-dimethyl-5-methoxytryptamine - 8-OH-DPAT 8-hydroxy-2[di-n-propylamino]tetralin - CYP cyanopindolol - DHE dihydroergotamine - DOI 2,5-dimethoxy-4-iodophenylisopropylamine - DP-5-CT N,N-dipropyl 5-carboxamidotryptamine - ICPY 2-iodo-cyanopindolol - mCPP m-chloro-phenyl-piperazine - TFMPP m-trifluoro-methyl-phenyl-piperazine - E_MAX Maximal effect - EC₅₀ Half maximal effective concentration - K_D Dissociation constant - K_B Antagonist dissociation constant     

The orphan receptor cDNA RDC4 encodes a 5-HT1D serotonin receptor.

The cDNA of RDC4, a putative receptor of the G protein-coupled receptor family, has been cloned by PCR methodology. The primary structure of this receptor showed homology with the serotonin 5-HT1A receptor. In this work, RDC4 mRNA has been injected in Y1 adrenal cells and Xenopus oocytes and RDC4 cDNA has been transfected transiently in cos-7 cells. In all these systems serotonin elicited a rise in cyclic AMP levels. Binding studies on membranes of the transfected cos-7 cells using [3H]-LSD showed a pattern of drug affinities consistent with the known properties of a 5-HT1D receptor. RDC4 therefore codes for a 5-HT1D receptor which in the studied systems is positively coupled to adenylate cyclase.     

Synthesis of potent and selective serotonin 5-HT1B receptor ligands

A series of serotonin 5-HT1B ligands were synthesized and evaluated for their potency and selectivity against other 5-HT receptor subtypes. Many of these new compounds displayed high affinity and selectivity for the 5-HT1B receptor and compound 6c was found to have the in vitro binding profile necessary for development as a PET radioligand.     

Novel 5-HT(1A/1B/1D) receptors antagonists with potent 5-HT reuptake inhibitory activity

Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.     

Synthesis and evaluation of 5-HT(2A) and 5-HT(2C) receptor binding affinities of novel pyrimidine derivatives

In an effort to find potential anxiolytic and/or antipsychotic agents with selective 5-HT(2C) affinity a series of new pyrimidine derivatives was prepared and the binding affinities for 5-HT(2A) and 5-HT(2C) receptors were determined.     

Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice

Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts.     

Binding of beta-carbolines at 5-HT(2) serotonin receptors

A series of ring-substituted (i.e., methoxy and bromo) 3,4-dihydro- and 1,2,3,4-tetrahydro-β-carbolines was examined at 5-HT_2A and 5-HT_2C serotonin receptors. Whereas most of the methoxy-substituted derivatives typically displayed affinities similar to their unsubstituted parents, certain (particularly 8-substituted) bromo derivatives displayed enhanced affinity. A binding profile was obtained for selected β-carbolines.     

5-Thienyltryptamine derivatives as serotonin 5-HT1B/1D receptor agonists: potential treatments for migraine

A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine.     

Bivalent ligand approach on 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine: synthesis and binding affinities for 5-HT(7) and 5-HT(1A) receptors

We here report on the synthesis and binding properties at 5-HT(7) and 5-HT(1A) receptors of ligands 3-12, that were designed according to the 'bivalent ligand' approach. Two moieties of the 5-HT(7)/5-HT(1A) ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (1) were linked through their 3-methoxy substituent by polymethylene chains of variable length, with the aim to increase the affinity for 5-HT(7) receptor and the selectivity over 5-HT(1A) receptors. In the best cases, the dimers showed affinities for 5-HT(7) receptors as high as the monomer with no improvement in selectivity. Some dimers displayed 5-HT(1A) receptor affinities slightly higher than monomer 1.     

New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsychotics sharing dopamine D(2)-receptor and serotonin 5-HT(1A)-receptor affinities

This paper describes the syntheses of several 1-aryl-4-(biarylmethylene)piperazines and the results of the determination of their affinity for D(2) and 5-HT(1A) receptors. A selection of these compounds was evaluated in vivo, resulting in the identification of a drug candidate which is being clinically evaluated as a potential atypical antipsychotic with reduced extrapyrimidal side effects.     

Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes.

We report the cloning and the deduced amino acid sequence of cDNAs encoding both the human serotonin 5-HT2 and 5-HT1C receptors. The human 5-HT2 and 5-HT1C receptors shared 87% and 90% amino acid homology, respectively, with their rat counterparts. The most divergent regions of the 5-HT2 receptor between human and rat were the N-terminal extracellular domain (75% homology) and the C-terminal intracellular domain (67% homology between amino acids 426-474). The greatest variability between the human and rat 5-HT1C receptors were at the N-terminal extracellular domain (78% homology) and the third cytoplasmic loop (71% homology). The availability of the cloned human 5-HT2 and 5-HT1C receptors will help facilitate the further understanding of the molecular pharmacology and physiology of these receptors.     

Imidazoline-modified benzylimidazolines as h5-HT(1D/1B) serotonergic ligands

Sumatriptan, a h5-HT1D and h5-HT1B receptor agonist used clinically as a migraine-abortive, produces certain side effects thought to result from its affinity for h5-HT1B receptors. The present investigation extends our work with benzylimidazolines as novel non-tryptamine h5-HT(1D/1B) ligands. The effect of N-methylation, N-benzylation, ring-aromatization, and variation of the imidazoline ring on affinity both at h5-HT1D and h5-HT1B receptors was examined. Several compounds were identified with good affinity and enhanced (i.e., > 100-fold) h5-HT1D versus hS-HT1B selectivity.     

Benzimidazolone-based serotonin 5-HT1A or 5-HT7R ligands: Synthesis and biological evaluation

A new group of serotoninergic 5-HT_1A or 5-HT₇ receptor ligands was identified. These compounds were designed and synthesized on a benzimidazolone scaffold and they enrich the well-known arylpiperazine class of 5-HT ligands. Diverse pharmacomodulations induced a shift in the affinity and selectivity profile with final identification of new potent hits.