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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin (5-HT) is a potent bioactive substance known to function through a number of different receptor types and subtypes. In our attempt to develop new agents that would interact selectively at certain 5-HT receptors, especially the 5-HT1A subtype, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) served as a template for the design of novel agents sharing aspects of the pharmacophore of 8-OH-DPAT and 5-HT. 5-HT contains no center of asymmetry, and 8-OH-DPAT shows only very modest stereospecificity for 5-HT1A receptors. To develop agents having enhanced potency and selectivity for the 5-HT1A site, several ring systems offering enhanced conformational rigidity which approximate the oxygen to nitrogen interatomic distances of 8-OH-DPAT and (to a lesser extent) 5-HT were synthesized. Exemplary ring systems include the 8-alkoxy-hexahydroindeno[1,2-c]pyrrole, 5-alkoxy-hexahydro-1H-indeno-[2,1-c]pyridine, and 9-alkoxy-hexahydro-1H-benz[e]isoindole systems. These conformationally restricted molecules demonstrated moderate stereospecificity in their interaction with the 5-HT1A binding site, which was enhanced in compounds with larger nitrogen substituents. Appropriate choice of such derivatives led to highly potent compounds selective for 5-HT1A sites compared with their activity at other 5-HT and/or adrenergic receptors. The pharmacological profile of compounds which appear to act as agonists at 5-HT1A receptors in the central nervous system to lower blood pressure in animal models of hypertension is presented.
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PMID:Molecular design of novel ligands for 5-HT1A receptors. 188 79

[1]Benzothieno[2,3-c]pyridines (10a-c, 11, 12a-t, and 13a,b) and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines (3a-c, 7, 8a-c, and 9) were synthesized. The compounds are bioisosteres of beta-carbolines and 1,2,3,4-tetrahydro-beta-carbolines where the indole nitrogen is replaced by sulfur. Their pharmacological activity was evaluated in a water lick conflict test in rats and a passive avoidance test in mice. In the 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine series, the presence of ethyl ester (3b) or cyclohexyl carboxamide (7) groups at C-3 conferred good anticonflict activity and lessening of memory impairment, while N-acylation of 3b abolished activity. In the [1]benzothieno(2,3-c]pyridine series, the aminoethyl carboxamide (12a) group at C-3 also conferred activity, but other amides studied were not active. The most potent compounds (3b, 7, and 12a) were also administered orally and had potent anticonflict and antiscopolamine amnesia-reversal activity. These compounds did not bind to the BZP receptor in spite of having structures similar to those of beta-carbolines. Compound 7 bound strongly to 5-HT1A receptors and would be expected to be a novel anxiolytic.
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PMID:Potent anticonflict activity and lessening of memory impairment with a series of novel [1]benzothieno[2,3-c]pyridines and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines. 197 11

A structure-activity analysis was used to identify selective 5-HT1A versus 5-HT1D receptor agents. An analysis of published data identified 13 drugs which display nanomolar affinity for the 5-HT1A receptor and that have been analyzed at 5-HT1D receptor binding sites. Four agents display greater than or equal to 100-fold selectivity for the 5-HT1A receptor. Two structural features were identified which hypothetically result in selectivity for 5-HT1A versus 5-HT1D binding sites. The linkage of an indole ring to a basic nitrogen atom via the 4 position on the indole ring or the absence of an indole ring are two features which lower the affinity for the 5-HT1D receptor, but do not necessarily lower the affinity for the 5-HT1A receptor. A series of 7 agents (5 indoles, 2 quinolines) was identified which met these hypothetical selectivity criteria. These compounds were then analyzed in radioligand binding studies. These 7 agents display affinities of 1.3-170 nM for the 5-HT1A receptor binding site, and 1,800-13,000 nM for the 5-HT1D receptor binding site. All 7 agents display greater than or equal to 47-fold selectivity for the 5-HT1A versus 5-HT1D site and 4 of the agents are greater than 100-fold selective. Compound No. 1 (N,N'-bis[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-meth ane) and compound No. 2 (N8-[3-(4-indolyloxy)-2-hydroxypropyl]-N1-(propioloyl)-(Z)-1 ,8-diamino-p-methane) are the most selective agents yet described for 5-HT1A versus 5-HT1D receptor binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structural determinants of 5-HT1A versus 5-HT1D receptor binding site selectivity. 206 May 96

A series of unsubstituted and substituted succinimido, maleimido, and glutarimidoethyl derivatives of eltoprazine (3) was synthesized and tested for affinity for the 5-HT1A receptor in rat brain homogenates. The unsubstituted compounds have a moderate affinity for the receptor, while the affinity considerably increases by substitution at or enlargement of these cyclic ring systems. A good correlation was found between the inhibition constant Ki (expressed as pKi) and the lipophilicity (clogP). No correlation was observed between the pKi or pKi+ (local inhibition constant) and the basicity of the N4-nitrogen atom.
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PMID:A series of N4-imidoethyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine as 5-HT1A receptor ligands: synthesis and structure-affinity relationships. 747 58

A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group (6-13) or an ethylenediamine chain (15-20) in position 2 were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT2A affinity are additive and could be described quantitatively. In a behavioral model it was also demonstrated that 6-11 are 5-HT2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d1 = 5.2-8.4 A, d2 = 5.7-8.5 A, and d3 = 4.6-7.3 A) define the molecular topography of the 5-HT2A receptor antagonists under study.
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PMID:Structure-activity relationship studies of CNS agents, Part 25. 4,6-di(heteroaryl)-2-(N-methylpiperazino)pyrimidines as new, potent 5-HT2A receptor ligands: a verification of the topographic model. 748 23

In order to explore the structural requirements for high 5-HT1A affinity, a series of aryl-substituted N1-phenylpiperazines were synthesized and evaluated for their ability to displace [3H]-8-OH-DPAT from its specific binding sites in rat frontal cortex homogenates. We found 2-methoxy substitution to be favorable, while 4-methoxy substitution was detrimental for 5-HT1A affinity. Substitution with annelated rings at the 2,3-positions was highly favorable for all investigated compounds, with the exception of a pyrrole ring. All other substitutions, except fluoro, in this class of heterobicyclic phenylpiperazines decreased affinity in the order: ortho > para > meta. The loss of affinity in the ortho and para positions is probably due to steric factors: the substituents either cause steric hindrance with the receptor or prevent the compound from adopting the appropriate conformation for binding to the 5-HT1A receptor. Conformational analysis combined with structure-affinity relationships (SAR) indicates that our arylpiperazines may bind at the 5-HT1A receptor in a nearly coplanar conformation. Observed interactions of the compounds in our 5-HT1A receptor model appeared to be in agreement with SAR data. The aromatic part of the arylpiperazine moiety has pi-pi interactions with the aromatic residues Trp161 and Phe362 in helices IV and VI, respectively. The positively charged protonated basic nitrogen forms a hydrogen bond with the negatively charged Asp116 in helix III. The ammonium-aspartate complex is surrounded by aromatic residues Trp358 and Phe361 in helix VI. A lipophilic pocket is formed by Phe362, Leu366 (both helix VI), and the methyl group of Thr200 (helix V). In agreement with the model, addition of a methyl substituent to the structure of the benzodioxine analogue 12 in this region, yielding 13, is favorable for 5-HT1A receptor affinity. Unfavorable positions for substitution with bulky groups, like the 3- and 4-positions in the benzofuran compound 14, are explained by steric hindrance with the backbone atoms of helix V. Thus, we were able to rationalize the 5-HT1A SAR of existing N1-phenylpiperazines, as well as a series of newly synthesized bicyclic heteroarylpiperazines, in terms of receptor-ligand interactions. Several of these N4-unsubstituted compounds had affinities in the low-nanomolar range.
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PMID:N4-unsubstituted N1-arylpiperazines as high-affinity 5-HT1A receptor ligands. 778 26

A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4-phenyl-1,2,3,6-tetrahydropyridines, and 4-phenylpiperazines was synthesized. The phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents. High affinity for both sigma 1 and sigma 2 binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT1A and 5-HT2A, dopamine D2, and adrenergic alpha 1 receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective sigma 2 ligands with subnanomolar affinity for the sigma 2 binding site. The prototype of such a compound was 1-(4-fluorophenyl)-3-[4-[4-(4-fluorophenyl)-1-piperidinyl]-1-butyl]-1H- indole, 11a (code no. Lu 29-253). This compound had the following binding affinities: IC50 (sigma 1) = 16 nM, IC50 (sigma 2) = 0.27 nM, IC50 (5-HT1A) = 22,000 nM, IC50 (5-HT2A) = 270 nM, IC50 (D2) = 4200 nM, IC50 (alpha 1) = 220 nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-piperdine] ring system resulted in even more selective compounds. Variations of the 1-substituent at the indole and of the chain length of the alkylene spacer group were studied. The optimal compound was the spiro analogue of compound 11a. This compound is 1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran- 1(3H),4'-piperidine], 14f (code no. Lu 28-179), with the binding affinities: IC50 (sigma 1) = 17 nM, IC50 (sigma 2) = 0.12 nM, IC50 (5-HT1A) = 21,000 nM, IC50 (5-HT2A) = 2000 nM, IC50 (D2) = 800 nM, IC50 (alpha 1) = 330 nM. However, the most selective sigma 2 versus sigma 1 ligand was the tropane derivative 1-(4-fluorophenyl)-3-[4-[3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2- en-8-yl]-1-butyl]-1H-indole, 15a. This compound had the following binding affinities: IC50 (sigma 1) = 1200 nM, IC50 (sigma 2) = 2.5 nM. Potent anxiolytic activity in the black/white box exploration test in rats was found with the two most prominent sigma 2 ligands Lu 29-253 and Lu 28-179. Good penetration into the CNS was documented both after subcutaneous and peroral administration of Lu 28-179 by ex vivo binding studies. Long duration of action was demonstrated both in ex vivo binding (T1/2 approximately 20 h) and in the black/white box exploration test.
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PMID:Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H-indoles. 778 31

Closely related analogs of the 5-HT1A receptor agonist cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9- carboxamide (1, U93385) were synthesized and pharmacologically evaluated. 9-Carboxamide analogs with varied nitrogen substitution (R2) were synthesized, and their serotonergic activity was evaluated in vitro and in vivo. Many of these compounds were incubated in the presence of rat hepatocytes, and the metabolic stability in vitro was compared to that of compound 1. Only the N-methyl and N-ethyl analogs ((-)-5a and (-)-5b) were more stable than compound 1, indicating that N-dealkylation is a major route of metabolism in this series. In addition, these analogs were found to be partial 5-HT1A receptor agonists in vivo. Modifications were also made to the carboxamide functionality of compound 1 (R1 in 2) to yield substituted amides or ketones. Among these analogs, the methyl ketone (-)-15a was found to be a 5-HT1A agonist with full intrinsic activity in vivo and was approximately 20 times more potent than compound 1 and 5 times more potent than 8-OH-DPAT.
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PMID:C-9 and N-substituted analogs of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3- propyl-1H-benz[e]indole-9-carboxamide: 5-HT1A receptor agonists with various degrees of metabolic stability. 786 20

Structure-affinity relationship (SAR) studies for the 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-aralkyl substituents: 4-aralkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). Their affinities for 5-HT1A receptors range from 0.15 to 28 nM and thus emphasize the importance of N4-substitution. By combining the SAR of these N4-aralkyl series with the recently published SAR of the N4-alkyl-substituted phenylpiperazines, the nature of the interaction of the N4-substituted phenylpiperazines and the 5-HT1A receptor was further examined using comparative molecular field analysis (CoMFA). To discriminate between two postulated hypotheses, CoMFA models were built and validated utilizing cross-validation, bootstrapping, and randomizing techniques. The model based on a N4-substituent alignment in which all N4-substituents are equally oriented in space was selected for further evaluation. According to the CoMFA/PLS analysis, the steric and electrostatic field properties contribute in a 98:2 ratio to the affinity found for the 5-HT1A receptor. Increasing steric bulk was found to be positively as well as negatively related to affinity depending on the distance of the bulk's center from the N4-nitrogen. The location of these steric CoMFA contour levels are well defined in space when the defined alignment rules are followed. Because CoMFA does not take hydrogen bonding into account, this could indicate that the contribution of the amide function (its ability to interact through hydrogen bonding), as present in the N4-substituents, to affinity is of minor importance.
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PMID:Structure-affinity relationship studies on 5-HT1A receptor ligands. 2. Heterobicyclic phenylpiperazines with N4-aralkyl substituents. 806 3

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.
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PMID:Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives. 809 37


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