Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three series of new unsubstituted or 2-acyl 1,2,3,4-tetrahydro-beta-carbolines (THBC), connected to 1-(o-methoxyphenyl)piperazine by 2-, 3- or 4-membered alkylene spacer (3, 4 or 5, respectively) in position 9, were synthesized and their 5-HT1A/5-HT2A receptor affinities and functional in vivo activities were investigated. Radioligand binding studies showed that unsubstituted (a) and acyl (b-f) derivatives with prop-1,3-ylene (4) and particularly with but-1,4-ylene (5) spacer had a high 5-HT1A receptor affinity (Ki = 30-110 nM), whereas the 5-HT1A affinity of derivatives with ethylene spacer (3) was low. All those compounds (except 5c, Ki = 44 nM) did not distinctly bind to 5-HT2A receptors. The obtained results indicated that the length of an alkylene chain was a crucial parameter for determining 5-HT1A receptor affinities of the tested compounds, while acyl substituents in position 2 of THBC were not important for their 5-HTIA/5-HT2A activities. It was also demonstrated that the few selected compounds (4d, 5a-c and 5e) with the highest affinity (Ki up to 50 nM) for 5-HT1A receptors, administered at doses of 10-20 mg/kg, behaved like antagonists of postsynaptic 5-HT1A receptors, as they reduced the 8-OH-DPAT (5-HT1A agonist)-induced lower lip retraction and behavioral syndrome in rats. Moreover, 4d seemed to be an agonist of presynaptic 5-HT1A receptors, since the hypothermia induced by its administration was attenuated by WAY 100635 (5-HT1A antagonist). Compound 5c, 5-HT2A receptor ligand, demonstrated an antagonistic activity, as it inhibited the (+/-)DOI (5-HT2A agonist)-induced head twitches in mice. The obtained results of in vivo studies suggest that introduction of different acyl substituents in position 2 of THBC with propylene or butylene spacer between tricyclous and arylpiperazine moiety is insignificant for the postsynaptic 5-HTIA receptor activity of the compounds tested in vivo. On the other hand, only compound 5c with an acryloyl group and a butylene chain behaved like a 5-HT1A/5-HT2A antagonist.
Pol J Pharmacol
PMID:2-H- and 2-acyl-9- [omega-[4-(2-methoxyphenyl)piperazinyl]-alkyl]-1,2,3,4-tetrahydro-beta-carbolines as ligands of 5-HT1A and 5-HT2A receptors. 1199 69

A series of omega-[4-(2-methoxyphenyl)piperazin-1-yl]alkyl derivatives with terminal pyrid-2(1H)-one fragments was synthesized and evaluated for their 5-HTIA and 5-HT2A activity. Enlargement of the aromatic amide system by its substitution with phenyl and/or p-methoxyphenyl in positions 4, 5 and/or 6, as well as modification of an aliphatic spacer allowed us to better understand structure-activity relationships in that group of compounds. The results of in vitro and in vivo experiments showed that only unsubstituted (1b) and monosubstituted (2b-4b) derivatives with the tetramethylene spacer demonstrated high 5-HTIA receptor affinity (Ki = 15-40 nM) and 5-HT1A/5-HT2A selectivity; they exhibited features of 5-HTIA antagonists. Those results suggested that the mode of substitution of the terminal amide moiety in the tested tetramethylene arylpiperazines was not significant for their 5-HTIA receptor activity. Conformational analysis calculations indicated that despite its great capacity for adaptation at 5-HTIA receptor site, an aryl substituent in position 4 in the pyrid-2(1H)-one ring destabilized the ligand-5-HT1A receptor complex formation in the case of trimethylene derivatives. Diarylsubstituted derivatives (5a-8a and 5b-8b) were characterized by a low 5-HT2A affinity (Ki > 446 nM) regardless of the spacer length, while those with the tetramethylene aliphatic chain had a higher 5-HT2A affinity than the remaining investigated compounds.
Pol J Pharmacol
PMID:Substitution mode of the amide fragment in some new N-[omega-[4-(2-methoxyphenyl)piperazin-1-yl]alkyl]pyrid-2(1H)-ones and their 5-HT1A/5-HT2A activity. 1199 83

A series of new 1,3-dimethyl-7-phenylalkyl-8-[3-(4-phenyl-1-piperazinyl)propylamino]-purine-2,6-dione derivatives (10-16) was synthesized and their 5-HTIA and 5-HT2A receptor affinities were determined. It was found that compounds with the phenylpropyl substituent in position 7 of purine-2,6-dione (12, 14 and 16), or with phenylmethyl in position 7 and 2-OCH3 in the phenylpiperazine part (13) showed a distinct affinity for 5-HTIA receptors (Ki = 8-50 nM). No structural modifications resulted in 5-HT2A ligands, since the affinity of 10-16 for those receptors was insignificant (Ki = 115-550 nM). The new 5-HT1A receptor ligands (12-14, 16) were investigated in vivo to determine their functional activity at those receptors. In behavioral studies, 12-14 and 16 behaved like postsynaptic 5-HTIA receptor antagonists, since they reduced lower lip retraction and the behavioral syndrome induced by 8-OH-DPAT (5-HT1A receptor agonist) in rats. When given alone, none of the compounds investigated in vivo, mimicked 8-OH-DPAT activity in those tests. Derivative 12 did not affect the body temperature in mice, whereas 13, 14 and 16 decreased it. Furthermore, 12 did not change the hypothermia induced by 8-OH-DPAT, and the decrease in body temperature in mice induced by 13, 14 or 16 was not antagonized by WAY 100635 (5-HT1A receptor antagonist); hence in that model neither 12, 13, 14 nor 16 acted as antagonists or agonists, respectively, at presynaptic 5-HT1A receptors.
Pol J Pharmacol
PMID:Synthesis, 5-HT1A and 5-HT2A receptor activity of new 1-phenylpiperazinylpropyl derivatives with arylalkyl substituents in position 7 of purine-2,6-dione. 1199 82

Mirtazapine (MIR) is an antidepressant drug which enhances noradrenergic and serotonergic 5-HT1A neurotransmission via antagonistic action at central alpha2-adrenergic autoreceptors and heteroreceptors. We reported earlier that tricyclic antidepressants administered repeatedly induced adaptive changes in the central dopaminergic D2/D3 receptors. Therefore, we designed our present study to determine whether repeated MIR treatment could evoke similar effect. The experiments were carried out on male Wistar rats. MIR was administered at a dose of 10 mg/kg once or repeatedly (twice daily for 14 days). The obtained results showed that MIR administered repeatedly potentiated the hyperlocomotion induced by D-amphetamine but not by quinpirole or 7-OH-DPAT. Biochemical study showed that MIR administered repeatedly decreased the binding of [3H]quinpirole (a D2/D3 receptor agonist) in the shell part of the nucleus accumbens septi and in the islands of Calleja but did not change the binding in the nucleus caudatus (medial or lateral). On the other hand, both acute and repeated drug treatment did not change the [3H]7-OH-DPAT (a D3 receptor agonist) binding sites in the islands of Calleja as well as in the shell part of nucleus accumbens septi. In addition, MIR did not alter the level of mRNA encoding dopamine D2 receptors, not only after repeated but also after acute treatment. The above results indicate that repeated MIR administration did not induce any adaptive change (behavioral and biochemical changes) in the dopaminergic D2/D3 system.
Pol J Pharmacol
PMID:Effect of repeated treatment with mirtazapine on the central dopaminergic D2/D3 receptors. 1252 92

In this study, we examined the role of 5-hydroxytryptamine (5-HT)1A and alpha1-adrenergic receptors in the hypothermia induced by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190) and its analogs, 1-(2-methoxyphenyl)-4-[(4-succinimido)butyl]piperazine (MM77) and trans-1(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]piperazine (MP245), which--like NAN-190--showed a high affinity for 5-HT1A and alpha1-adrenoceptors. Administration of NAN-190 (a partial agonist of presynaptic and an antagonist of postsynaptic 5-HT1A receptors and alpha1-adrenoceptors), MM77 and MP245 (antagonists of postsynaptic 5-HT1A receptors), as well as 8-OH-DPAT (a 5-HT1A agonist) and prazosin (an alpha1-adrenoceptor antagonist) induced a dose-dependent hypothermia in mice. The silent antagonist of 5-HT1A receptors, WAY 100635, which abolished the hypothermic effect of 8-OH-DPAT, inhibited the hypothermia induced by NAN-190 administered at a dose of 1 mg/kg (but not 2 mg/kg) and by MP245 (0.5 and 1 mg/kg), but failed to change the MM77 (1 and 4 mg/kg)-induced decrease in body temperature in mice. The alpha1-adrenoceptor agonist St 587, which reduced the hypothermic effect of prazosin, inhibited the decrease in body temperature evoked by NAN-190 at the higher dose and by MP245 at both the doses used, but did not affect the MM77-induced hypothermia in mice. The obtained results suggest that the hypothermia in mice induced by NAN-190 and its constrained analog MP245 is connected with stimulation of 5-HT1A receptors and with blockade of alpha1-adrenoceptors, participation of these receptors not being equivalent, though. The origin of the hypothermia evoked by MM77 is still unknown.
Pol J Pharmacol
PMID:Pharmacological analysis of the hypothermic effects of NAN-190 and its analogs, postsynaptic 5-HT1A receptor antagonists, in mice. 1252 93

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.
Pol J Pharmacol
PMID:Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats. 1286 16

In vivo microdialysis in conscious rats was used to evaluate the effect of 5-HT1A agonist (+/-)-8-hydroxy-2-(n-dipropylamino)tetralin (8-OH-DPAT), 5-HT2A/2C agonist (+/-)- 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo-[3,2-b]pyrid-5-one (CP 93129) on the veratridine-evoked glutamate (Glu) and aspartate (Asp) release in the rat prefrontal cortex. CP 93129 at concentrations between 50-500 microM significantly reduced Glu and Asp release. The effect of CP 93129 was attenuated by intraperitoneal (ip) administration of the selective 5-HT1B receptor antagonist N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[ 1, 1'-biphenyl]-4-carboxamide (SB 216641) at a dose of 2 mg/kg. Neither DOI (100 microM) nor 8-OH-DPAT given locally at concentration of 100 microM or peripherally at doses of 0.1 and 1 mg/kg ip, influenced stimulated Glu and Asp release. We suggest that cortical glutamatergic neurons possess 5-HT1B heteroceptors and their activation may be responsible for the inhibitory effect of 5-HT on Glu and Asp release.
Pol J Pharmacol
PMID:Inhibition of amino acid release by 5-HT1B receptor agonist in the rat prefrontal cortex. 1286 17

Novel omega-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl derivatives 1-6 containing 4-, 5- and/or 6-arylsubstituted pyrid-2(1H)-one moiety were synthesized. All the new compounds were examined in vitro to assess their 5-HT1A and 5-HT2A receptor affinities. Compounds 3 and 4 with a 5- or a 6-phenylsubstituted pyridone ring demonstrated high 5-HT1A receptor affinity (Ki = 17 and 38 nM, respectively) and were tested in behavioral functional models. Derivative 3 can be regarded as a weak 5-HT1A postsynaptic antagonist, whereas 4 showed features of a weak partial agonist of 5-HT1A receptors (an agonist of pre- and an antagonist of postsynaptic ones). Binding affinities and in vivo results were discussed in comparison with those for the previously described tetramethylene analogs. The obtained results showed that the shortening of the aliphatic chain to two methylene groups exposed the intrinsic activity of the ligand 4 at 5-HT1A receptor sites.
Pol J Pharmacol
PMID:Novel N-[omega-[4-(2-methoxyphenyl)piperazin-1-yl]-ethyl]pyrid-2(1H)-ones with diversified 5-HT1A receptor activity. 1286 19

Two series of 4-alkyl-1-arylpiperazines (1-4) and 1,2,3,4-tetrahydroiso-quinolines (5, 6) with diphenylmethylamino (series a) or diphenylmethoxy (series b) fragment were synthesized in order to obtain potential ligands of 5-HT1A and/or 5-HT2A and dopamine D2 receptors. Four new arylpiperazines (1a, 3a, 1b, 3b) were found to demonstrate high 5-HT1A receptor affinity (Ki = 1.5-35 nM); among them, 3a exhibited satisfactory 5-HT2A receptor affinity (Ki = 74 nM). Only compounds 1b and 2b showed moderate affinity for D2 receptor sites (Ki = 123 and 128 nM, respectively). Compounds 1a, 3a, 1b and 3b were investigated in vivo to determine their functional activity at 5-HT1A receptors; additionally, 3a was tested for 5-HT2A receptor activity. Derivatives 1a, 1b and 3b produced effects characteristic of antagonists of postsynaptic 5-HT1A receptors. Moreover, 1b exhibited features of an agonist of presynaptic 5-HT1A receptors, while 3a behaved like a partial agonist of postsynaptic 5-HT1A sites. The latter derivative may also be classified as a 5-HT2A receptor antagonist. Thus, novel potent 5-HT1A receptor ligands were successfully obtained, and the most promising compound 3a showed mixed 5-HT1A/5-HT2A receptor activity in in vitro and in vivo tests.
Pol J Pharmacol
PMID:Novel 4-alkyl-1-arylpiperazines and 1,2,3,4-tetrahydroisoquinolines containing diphenylmethylamino or diphenylmethoxy fragment with differentiated 5-HT1A/5-HT2A/D2 receptor activity. 1458 12

Novel N-[3-(4-phenylpiperazin-1-yl)-propyl] derivatives of 3-spiro-cyclo-hexanepyrrolidine-2,5-dione (5-7) and 3-spiro-beta-tetralonepyrrolidine-2,5-dione (8-10) were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. All tested compounds exhibited moderate to low 5-HT1A receptor affinity, whereas compounds 5-7 demonstrated high 5-HT2A receptor affinity (Ki = 27, 46 and 15 nM, respectively) and features of 5-HT2A receptor antagonists. Introduction of a beta-tetralone fragment in the 3-position of pyrrolidine-2,5-dione ring (8-10) did not affect 5-HT1A but decreased 5-HT2A receptor affinity.
Pol J Pharmacol
PMID:Synthesis and 5-HT1A/5-HT2A receptor activity of new N-[3-(4-phenylpiperazin-1-yl)-propyl] derivatives of 3-spiro-cyclohexanepyrrolidine-2,5-dione and 3-spiro-beta-tetralonepyrrolidine-2,5-dione. 1458 13


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