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1.
Bioorg Med Chem Lett ; 11(17): 2345-9, 2001 Sep 03.
Article in English | MEDLINE | ID: mdl-11527728
2.
Bioorg Med Chem ; 7(11): 2541-8, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10632064

ABSTRACT

Eight new C5-substituted derivatives of the potential atypical antipsychotic agent 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 1) have been prepared by chemical conversion of the 5-trifluoromethylsulfonyloxy (triflate) analogue 4 via various Stille-type cross-couplings, a Heck reaction, and an amidation in moderate to good yields. The 5-acetyl, 5-cyano, 5-methyl, 5-(2-furyl), 5-phenyl, methyl 5-carboxylate, and the 5-carboxamido analogues 5-11 thus obtained, the previously disclosed 5-methoxy, 5-hydroxy, and 5-unsubstituted analogues 1-3, and the 5-triflate analogue 4 were evaluated for their ability to compete for [3H]-spiperone binding to rat striatal membranes containing dopamine D2 receptors, and their ability to compete for [3H]-8-OH-DPAT binding to rat frontal cortex membranes containing serotonin 5-HT1A receptors in vitro. Compounds 1-11 displayed weak to high affinities for dopamine D2 receptors, with Ki-values ranging from 550 nM for the 5-carboxamido analogue to 4.9 nM for the 5-hydroxy analogue. The relative affinities of the 5-methoxy, 5-hydroxy, and 5-unsubstituted analogues suggested that these compounds may bind to the same site and in a similar way as the 5-oxygenated DPATs, with the 5-methoxy substituent of 1 functioning as a hydrogen bond acceptor. The serotonin 5-HT1A receptor tolerated more structural diversity at the C5-position of 1, as revealed by the higher Ki-values of 1-11, which ranged from 60 nM for the 5-carboxamido analogue to 1.0 nM for the 5-unsubstituted analogue. Partial least-squares (PLS) analysis of a set of 24 molecular descriptors, generated for each analogue, revealed no significant correlation between the dopamine D2 receptor affinities of 1-11 and their molecular properties, supporting the view that they may have different binding modes at this receptor subtype. A PLS model with moderate predictability (Q2 = 0.49) could be derived for the serotonin 5-HT1A receptor affinities of 1-11. According to the model, a relatively lipophilic, nonpolar C5-substituent should be optimal for a high affinity at this receptor subtype.


Subject(s)
Benzamides/chemistry , Dopamine Agents/chemical synthesis , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Tetrahydronaphthalenes/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/pharmacology , Dopamine Agents/pharmacology , In Vitro Techniques , Male , Rats , Rats, Wistar , Receptors, Dopamine D2/drug effects , Receptors, Serotonin/drug effects , Receptors, Serotonin, 5-HT1 , Structure-Activity Relationship , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology
3.
Bioorg Med Chem ; 6(11): 2103-10, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9881100

ABSTRACT

The high-pressure Diels-Alder reaction of N-carbomethyoxypyrroles and phenyl vinyl sulfone affords versatile intermediates for the palladium-catalyzed preparation of new epibatidine analogues. Structure-activity relationships of new epibatidine analogues are presented. High affinities of Ki = 0.81 and 2.6 nM for the [3H]-cytisine rat brain nicotinic acetylcholine binding sites were found for the 5-pyrimidinyl and the 5-(2-amino)-pyrimidinyl epibatidine analogues, respectively.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Nicotinic Agonists/chemical synthesis , Pyridines/chemistry , Pyridines/chemical synthesis , Receptors, Nicotinic/metabolism , Alkaloids/metabolism , Animals , Azocines , Binding, Competitive , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Membrane/metabolism , Drug Design , Indicators and Reagents , Kinetics , Models, Molecular , Molecular Conformation , Molecular Structure , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Quinolizines , Rats , Receptors, Nicotinic/drug effects , Structure-Activity Relationship
4.
J Med Chem ; 40(3): 300-12, 1997 Jan 31.
Article in English | MEDLINE | ID: mdl-9022796

ABSTRACT

We investigated the structural requirements for high 5-HT1A affinity of the agonist flesinoxan and its selectivity versus D2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [3H]-8-OH-DPAT and [3H]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N4-substituent and the arylpiperazine region. Effects of N4-substitution in the investigated compounds appeared to be quite similar for 5-HT1A- and D2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N4 atom seems to be the main contributing factor to affinity for both receptors. Our data show that the amide group in the flesinoxan N4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N4-substituents, selectivity for 5-HT1A versus D2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N4-[(p-fluorobenzoyl)amino]ethyl substituent is probably directed anti-periplanar relative to the HN4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we previously reported. Amino acid residues surrounding the N4-[(p-fluorobenzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D2 receptors. These observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D2 receptors.


Subject(s)
Piperazines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/metabolism , Amino Acid Sequence , Animals , Binding Sites , Binding, Competitive , Brain/metabolism , CHO Cells , Cricetinae , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Sequence Data , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/metabolism , Protein Binding , Rats , Receptors, Serotonin, 5-HT1 , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Spiperone/metabolism , Structure-Activity Relationship
5.
Br J Pharmacol ; 116(4): 2315-21, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8564266

ABSTRACT

1. In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2. IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-alpha-methylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2 = 9.12 +/- 0.06, Schild slope: 1.0 +/- 0.1, n = 8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 +/- 0.2). 3. In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]-IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 +/- 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1- and H2 receptor. Displacement of [3H]-mepyramine and [125I]-iodoaminopotentidine binding to respectively guinea-pig H1- and human H2 receptors by IPP resulted in Ki values of 1.71 +/- 0.32 microM (n = 3) and 2.28 +/- 0.81 microM (n = 3). For thioperamide the affinities for the H1-, H2- and H3 receptor were respectively > 10 microM, > 10 microM and 4.3 +/- 1.6 nM (n = 7). 4. Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5-hydroxytryptamine 5-HT3 receptor (Ki = 11 +/- 1 nM, n = 3), the alpha 2-adrenoceptor (Ki = 120 +/- 5 nM, n = 3) and the sigma receptor (Ki = 170 +/- 70 nM, n = 3). Thioperamide showed relatively high affinity for the 5-HT3 receptor (Ki = 120 +/- 30 nM, n = 3) and the sigma receptor (Ki = 180 +/- 90 nM, n = 3). 5. Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha 2- and the sigma receptor might interfere with [125I]-IPP binding to rat cortex membranes. Yet, in this preparation [125I]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol. The interaction with the 5-HT3 receptor was not restricted to IPP or thioperamide, but was alsofound with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belongingto the same chemical class of IPP, also interacted with the 5-HT3 receptor (Ki = 240 +/- 40 nM). In contrast,histamine or the H3 receptor agonist, (R)-a-methylhistamine showed no affinity for the 5-HT3 receptor.7 In the guinea-pig isolated ileum, imetit evoked concentration-dependent contractions, resulting in apD2 value of 4.72 +/- 0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 valueof 7.1 +/- 0.1 (n = 9). Similarly ondansetron antagonized the contractions evoked by the 5-HT3 receptoragonist, 2-methyl-5-HT with a pA2 value of 7.3 +/- 0.1 (n = 4). IPP and thioperamide did not mimic 2-methyl-5-HT but non-competitively inhibited the 2-methyl-5-HT-induced contractions of thispreparation.8 In an in vivo model for 5-HT3 activity, the Von Bezold Jarisch reflex, thioperamide showedantagonism in low dosages, which correlated well with the affinity for the 5-HT3 receptor site. Yet, athigher dosages no further 5-HT3 receptor antagonism was observed. For IPP no 5-HT3 receptor activitycould be observed in vivo.9 In the present study we showed that many H3 receptor compounds, that are regarded as highlyselective (including the prototype drug, thioperamide), also interact with the 5-HT3 receptor, albeit athigher drug concentrations.Keywords.: Histamine H3-receptor; iodophenpropit; thioperamide; receptor selectivity; 5-hydroxytryptamine 5-HT3 receptor;guinea-pig intestine; rat brain; Von Bezold Jarisch reflex


Subject(s)
Histamine Antagonists , Imidazoles/pharmacology , Isothiuronium/analogs & derivatives , Piperidines/pharmacology , Receptors, Serotonin/drug effects , Animals , Binding, Competitive/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Guinea Pigs , Histamine Agents/pharmacology , Histamine Antagonists/pharmacology , Ileum/drug effects , Ileum/metabolism , In Vitro Techniques , Isothiuronium/pharmacology , Jejunum/drug effects , Jejunum/metabolism , Male , Muscle Contraction/drug effects , Rats , Rats, Wistar , Reflex/drug effects , Serotonin Antagonists/pharmacology
6.
J Med Chem ; 38(21): 4303-8, 1995 Oct 13.
Article in English | MEDLINE | ID: mdl-7473558

ABSTRACT

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.


Subject(s)
Piperazines/chemistry , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , 8-Hydroxy-2-(di-n-propylamino)tetralin/metabolism , Animals , Binding Sites , Brain/metabolism , Cyclization , Frontal Lobe/metabolism , Hydrogen-Ion Concentration , Lipid Metabolism , Molecular Structure , Rats , Serotonin Receptor Agonists/metabolism , Stereoisomerism , Structure-Activity Relationship
7.
J Med Chem ; 38(11): 1942-54, 1995 May 26.
Article in English | MEDLINE | ID: mdl-7783126

ABSTRACT

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.


Subject(s)
Piperazines/chemistry , Piperazines/metabolism , Receptors, Serotonin/metabolism , 8-Hydroxy-2-(di-n-propylamino)tetralin/metabolism , Amino Acid Sequence , Animals , Binding Sites , Chemical Phenomena , Chemistry, Physical , Molecular Conformation , Molecular Sequence Data , Molecular Structure , Piperazines/chemical synthesis , Protein Conformation , Radioligand Assay , Rats , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Structure-Activity Relationship
8.
J Med Chem ; 37(17): 2761-73, 1994 Aug 19.
Article in English | MEDLINE | ID: mdl-8064803

ABSTRACT

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.


Subject(s)
Piperazines/chemistry , Piperazines/metabolism , Receptors, Serotonin/metabolism , Animals , Computer Graphics , Frontal Lobe/metabolism , Indicators and Reagents , Kinetics , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Radioligand Assay , Rats , Receptors, Serotonin, 5-HT1 , Structure-Activity Relationship
9.
Eur J Pharmacol ; 256(2): 141-7, 1994 Apr 21.
Article in English | MEDLINE | ID: mdl-8050464

ABSTRACT

Using a two-lever operant drug discrimination procedure, rats were trained to discriminate the 5-HT1A receptor agonist, flesinoxan (0.5 mg/kg i.p.), from saline. Hereafter, several non-serotonergic drugs were tested in generalization and antagonism tests. The flesinoxan stimulus did not generalize to the stimuli of either the alpha 1-adrenoceptor antagonist, prazosin, the alpha 2-adrenoceptor agonist, clonidine, the dopamine receptor agonist, apomorphine, the dopamine receptor antagonists, haloperidol and pimozide, the benzodiazepine receptor agonist, chlordiazepoxide, nor to the peripherally acting vasodilator, hydralazine. In antagonism studies, prazosin, haloperidol, pimozide and the alpha 2-adrenoceptor antagonist, idazoxan, failed to block the flesinoxan stimulus. In substitution tests, however, flesinoxan partially generalized to idazoxan and completely to the alpha 2-adrenoceptor antagonist, yohimbine. The affinities of yohimbine and idazoxan for the 5-HT1A receptor may explain the latter result. The present findings suggest that the central mechanism through which flesinoxan exerts its discriminative stimulus effects does not involve alpha 1- and alpha 2-adrenoceptors, dopamine and benzodiazepine receptors. Finally, the results with the blood pressure lowering agents, hydralazine, clonidine and prazosin do not support the suggestion that the centrally mediated blood pressure lowering effects of flesinoxan contribute to its internal stimulus effect.


Subject(s)
Discrimination, Psychological/drug effects , Piperazines/pharmacology , Receptors, Adrenergic/drug effects , Receptors, Dopamine/drug effects , Serotonin Receptor Agonists/pharmacology , Animals , Blood Pressure/drug effects , Chlordiazepoxide/pharmacology , Conditioning, Operant/drug effects , Generalization, Stimulus/drug effects , Hydralazine/pharmacology , Male , Piperazines/antagonists & inhibitors , Rats , Rats, Wistar , Serotonin Receptor Agonists/antagonists & inhibitors
10.
Br J Pharmacol ; 111(2): 497-502, 1994 Feb.
Article in English | MEDLINE | ID: mdl-7911716

ABSTRACT

1. In the immature rat in vitro hemisected spinal cord preparation the dorsal root-evoked depolarizing potential recorded from an adjacent dorsal root DR-DRP had a mean peak amplitude (+/- s.e.mean, n = 27) of 2.9 +/- 0.2 mV and a mean latency to peak amplitude of 106 +/- 3 ms. The DR-DRP amplitude was maximal with a stimulus intensity of four times the threshold intensity required to activate the lowest threshold fibres. The peak amplitude and/or integral over a time-source of 0.5 s were used to assess the effects of applied drugs. 2. The DR-DRP was abolished by baclofen (mean IC50 190 +/- 46 nM, n = 7). The depressant effect of baclofen was reversed by CGP35348 (1 mM). The mean apparent Kd value calculated from dose-ratios was 16.7 +/- 6.4 microM (n = 3). 3. At a maximally effective concentration, tizanidine (1 microM) produced at the most only a 14% depression of the DR-DRP (n = 4). Clonidine (0.3 microM) had an effect similar to that of tizanidine. These depressant effects were reversed by idazoxan (1 microM). 4. The DR-DRP was potentiated by diazepam in a flumazenil (1 microM)-reversible manner. A maximal potentiation of 23.2 +/- 2.7% (n = 5) was produced by 1 microM diazepam. 5. Diazepam (1 microM) induced a mean bicuculline- (10 microM, n = 2) and flumazenil- (1 microM, n = 8) sensitive depolarization in the dorsal root of 0.25 +/- 0.03 mV (n = 8). However, diazepam failed to depolarize dorsal roots (n = 3) which had been excised from the spinal cord. 6. Comparison of the above effects with previously reported depressant effects of these drugs on the synaptic output from ventral roots suggests that actions on presynaptic inhibition, as reflected in the DR-DRP, are of subsidiary importance in explaining the muscle relaxant actions of tizanidine or diazepam.


Subject(s)
Muscle Relaxants, Central/pharmacology , Neurons, Afferent/drug effects , Spinal Cord/drug effects , Synapses/physiology , 2-Amino-5-phosphonovalerate/pharmacology , Adrenergic alpha-Agonists/pharmacology , Animals , Baclofen/pharmacology , Clonidine/analogs & derivatives , Clonidine/pharmacology , Diazepam/pharmacology , Electric Stimulation , Evoked Potentials/drug effects , Ganglia, Spinal/cytology , Ganglia, Spinal/drug effects , In Vitro Techniques , Nerve Fibers/drug effects , Rats , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/physiology , Spinal Cord/cytology
11.
J Med Chem ; 36(23): 3693-9, 1993 Nov 12.
Article in English | MEDLINE | ID: mdl-8246239

ABSTRACT

On the basis of the structures of ondansetron and GR 65,630, its ring-opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT3 antagonists. Receptor binding studies show that all compounds display a high affinity for the 5-HT3 receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyri do [3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (Ki = 0.19 nM), a weak affinity for sigma-receptors (Ki = 340 nM), muscarine M1 receptors (Ki = 910 nM), and 5-HT4 receptors (Ki = 960 nM) and no affinity (Ki > or = 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT3 receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.


Subject(s)
Carbazoles/chemical synthesis , Imidazoles/chemistry , Indoles/chemistry , Indoles/chemical synthesis , Ondansetron/chemistry , Pyridines/chemical synthesis , Serotonin Antagonists , Animals , Carbazoles/pharmacology , Cell Membrane/metabolism , Cerebral Cortex/metabolism , Guinea Pigs , Ileum/drug effects , Ileum/physiology , Indoles/metabolism , Models, Molecular , Molecular Conformation , Molecular Structure , Pyridines/pharmacology , Rats , Receptors, Serotonin/metabolism , Stereoisomerism , Structure-Activity Relationship , Vagus Nerve/drug effects , Vagus Nerve/physiology
12.
J Med Chem ; 36(19): 2751-60, 1993 Sep 17.
Article in English | MEDLINE | ID: mdl-8410989

ABSTRACT

Structure-affinity relationship (SAR) studies for 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-alkyl substituents: 4-alkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl were synthesized and evaluated for their ability to displace [3H]-2-(di-n-propylamino)-8-hydroxytetralin from its specific binding sites in rat frontal cortex homogenates. All compounds displayed a nanomolar affinity for the 5-HT1A receptor. In both series the N-ethyl and N-n-propyl substituted derivatives have similar affinities, being slightly but statistically significantly less active than the N-methyl-substituted derivatives. Elongation of the hydrocarbon chain increases the affinity for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (Ki = 0.50 nM) and 39 (Ki = 0.54 nM). Assuming that the arylpiperazine derivatives at the 5-HT1A binding site are in the ionic state, ionization constants were determined in order to evaluate the use of the local inhibition constant, Ki+, as a more convenient parameter to study the structure-affinity relationships. However, the Ki+ could not account for the specific N4-substituent effects found.


Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Piperazines/chemical synthesis , Receptors, Serotonin/metabolism , Animals , Binding Sites , Brain/drug effects , Brain/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/metabolism , Piperazines/chemistry , Piperazines/metabolism , Rats , Structure-Activity Relationship
13.
Acta Neuropsychiatr ; 4(2): 40-5, 1992 Jun.
Article in English | MEDLINE | ID: mdl-26956533

ABSTRACT

Serotonin (5-HT) plays an important role in depression and specific 5-HT reuptake blockers appear to be clinically important antidepressants. It is unclear however, which serotonergic mechanism is involved in the antidepressant effect, certainly when regarding the existence of at least seven 5-HT receptor subtypes. By testing different 5-HT ligands in two animal models of depression (forced swimming and DRL72-S test) and comparison with data from literature, evidence is provided for potential antidepressant qualities of 5-HT1A receptor-agonists and 5-HT1C receptor-antagonists. Compounds binding to 5-HT1B, 5-HT2 and 5-HT3 receptors do not have an antidepressant profile. Results of clinical research support the predicted antidepressive effects of 5-HT1A receptor-agonists.

14.
Vet Rec ; 129(19): 427-9, 1991 Nov 09.
Article in English | MEDLINE | ID: mdl-1776223

ABSTRACT

The effects of an oral isoxsuprine-resin preparation on the blood flow in the thoracic limb of seven horses was determined by thermography. Treatment with the oral resin preparation resulted in increased skin temperatures compared with the non-medicated controls. The maximal temperature differences, 2.2 degrees C for the horses treated with 0.9 mg/kg and 1.8 degrees C for the horses treated with 1.2 mg/kg, occurred four hours after dosing. Plasma total isoxsuprine, determined in three horses, was detectable two hours after oral dosing and maximal eight hours after dosing, but free isoxsuprine could not be detected. Receptor binding studies demonstrated strong alpha-receptor binding, and this binding was so strong that even at isoxsuprine concentrations below the detection level receptors could have been stimulated.


Subject(s)
Forelimb/blood supply , Horses/physiology , Isoxsuprine/pharmacology , Animals , Body Temperature , Female , Male , Regional Blood Flow/drug effects , Skin Temperature , Thermography/veterinary
15.
Pharmacol Biochem Behav ; 40(2): 345-9, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1805238

ABSTRACT

In this study, the affinity profile of idaverine for the M1- (neuronal tissue), M2- (heart) and M3- (glandular tissue/nonvascular smooth muscle) muscarinic receptors was examined by means of radioligand binding and in vitro organ bath experiments in order to use the compound for the investigation of the muscarinic receptor subtype involved in motion sickness. In the profile study a comparison was made with the muscarinic antagonists atropine, pirenzepine (M1-selective) AF-DX 116 (M2-selective) and 4-DAMP (high affinity for M1- and M3-binding sites). The affinity of idaverine appeared to be equally high for the M1- and M2-binding sites. However, the affinity for the M1-binding sites should be interpreted cautiously since the Hill slope deviated from unity. Idaverine showed a 20-fold selectivity for the M2-binding sites over the M3-binding sites, whereas it showed a small selectivity (less than 5-fold) for the M2-receptors compared to the ileal and tracheal smooth muscle receptors. Thus idaverine appears to be M2 over M3 selective. However, in contrast to AF-DX 116, it is not clear whether idaverine is also M2 over M1 selective. In experiments with cats, idaverine failed to prevent motion sickness at doses from 0.03 to 3 mg/kg. These results are interpreted to implicate M3-receptors in the motion sickness suppressant effect of antimuscarinic drugs.


Subject(s)
Isonipecotic Acids/pharmacology , Motion Sickness/prevention & control , Muscarinic Antagonists , Animals , Brain Chemistry/drug effects , Cats , Cattle , Female , In Vitro Techniques , Isonipecotic Acids/therapeutic use , Male , Muscle, Smooth/drug effects , Myocardial Contraction/drug effects , Myocardium/metabolism , Parasympatholytics/pharmacology , Radioligand Assay , Rats , Rats, Inbred Strains
16.
J Recept Res ; 11(6): 891-907, 1991.
Article in English | MEDLINE | ID: mdl-1661335

ABSTRACT

Amiloride and its analogues affect radioligand binding to the adenosine-A1 receptor. In this paper, the specificity of this effect is investigated by generating receptor binding profiles for amiloride and two of its analogues. A limited structure-activity relationships study is performed to probe the relationship between inhibition of receptor binding by amiloride analogues and the effects of these compounds on Na+ transport, in particular Na+/H+ exchange. The receptor binding profiles of amiloride, benzamil and 5'-(N,N-hexamethylene)amiloride (HMA) indicate that the compounds affect a variety of receptors and that none of the compounds is highly selective for any of these. The SAR study indicates that it is very unlikely that a direct coupling between receptors and Na+/H+ exchange or another amiloride-sensitive ion transport system is responsible for the inhibition of receptor binding. A correlation between the signal transduction systems coupled to the receptors involved and the potency of the amiloride analogues is also absent. The varying nature of the receptors, affected by amiloride or its analogues, suggests a wide-spread presence of an amiloride binding site on receptors and other membrane proteins.


Subject(s)
Amiloride/analogs & derivatives , Amiloride/metabolism , Receptors, Cell Surface/metabolism , Sodium/metabolism , Amiloride/pharmacology , Animals , Binding Sites , GTP-Binding Proteins/metabolism , Rats , Structure-Activity Relationship
17.
Eur J Pharmacol ; 188(6): 301-12, 1990 Jun 12.
Article in English | MEDLINE | ID: mdl-2164935

ABSTRACT

Since the demonstration that serotonin (5-hydroxytryptamine, 5-HT) interacts with different (sub)types of membrane receptors, several compounds have been proposed as potent and selective ligands for one of these 5-HT subtypes. Unfortunately, specific and highly selective ligands (selectivity ratios greater than or equal to 1000) for the majority of 5-HT subtypes are still lacking. A few compounds are selective (ratios greater than or equal to 100), but most of the reputed 'selective' tools display affinities for other 5-HT subtypes and/or other (neuro-) transmitter receptors. Mainly due to different interpretations of the concept of selectivity, many of these nonselective compounds are still used to characterize 5-HT receptors. In this paper, we present the affinities (obtained by radioligand binding studies) of the most selective tools known today for each of the 5-HT subtypes and discuss the structure-activity relationships of some interesting series. The potential use of several of these selective ligands as pharmacological tools and therapeutics will be briefly reviewed.


Subject(s)
Receptors, Serotonin/drug effects , Animals , Humans , Radioligand Assay , Receptors, Neurotransmitter/metabolism , Stereoisomerism , Structure-Activity Relationship
18.
Drug Metabol Drug Interact ; 8(1-2): 85-114, 1990.
Article in English | MEDLINE | ID: mdl-1982626

ABSTRACT

In this paper we present the neurochemical profile of eltoprazine, a drug that specifically inhibits offensive aggression. Eltoprazine interacts selectively with serotonin (5-HT) receptor subtypes (Ki-values for 5-HT1A, 5-HT1B and 5-HT1C receptors are 40, 52 and 81 nM respectively). Affinity for other neurotransmitter receptors is much lower (Ki-values greater than 400 nM) than for 5-HT1 receptors. The selective interaction with 5-HT1 receptor subtypes is confirmed by in vitro autoradiographic studies using radiolabelled eltoprazine. The overall distribution of [3H]eltoprazine bears a strong resemblance to the localization of 5-HT1 binding sites labelled by [3H]5-HT, although some differences are observed. Eltoprazine (1 microM) inhibits the forskolin stimulated c-AMP production in hippocampus slices of the rat, indicating an agonistic action on the 5-HT1A receptor. The K+ stimulated release of 5-HT from rat cortex slices is inhibited by eltoprazine (pD2 = 7.8). The maximal response, however, was clearly less than that of the full agonist 5-HT, indicating partial agonistic activity on the 5-HT1B receptor (alpha = 0.5). Eltoprazine has a weak antagonistic action (IC50 = 7 microM) on the 5-HT1C receptor as revealed by inhibition of the 5-HT-induced accumulation of inositol phosphates in the choroid plexus of the pig. In vivo, eltoprazine reduces 5-HIAA levels in the striatum, without affecting the 5-HT levels. Eltoprazine also reduces the 5-HT synthesis rate as shown by 5-HTP accumulation after decarboxylase inhibition. These data indicate that eltoprazine acts as a 5-HT agonist in vivo in a dose range that affects aggressive behaviour (0.3-3 mg/kg p.o.). Taken together from a variety of neurochemical studies there is strong evidence both in vitro and in vivo that the pharmacological actions of eltoprazine can be attributed to an interaction with the 5-HT system, most probably via a (partial) agonistic action on 5-HT1A and 5-HT1B receptors.


Subject(s)
Brain/metabolism , Piperazines/pharmacology , Psychotropic Drugs/pharmacology , Animals , Binding Sites , Biogenic Monoamines/metabolism , Brain/drug effects , Brain/ultrastructure , Corpus Striatum/metabolism , Male , Neurons/chemistry , Neurotransmitter Agents/physiology , Phosphatidylinositols/metabolism , Piperazines/metabolism , Piperazines/pharmacokinetics , Rats , Rats, Inbred Strains , Receptors, Serotonin/metabolism , Receptors, Serotonin/physiology , Second Messenger Systems , Serotonin/metabolism , Serotonin/pharmacokinetics , Serotonin/physiology , Serotonin Antagonists , Swine , Tissue Distribution , Tritium
19.
J Neural Transm Gen Sect ; 78(1): 73-87, 1989.
Article in English | MEDLINE | ID: mdl-2547025

ABSTRACT

The aim of this study was to investigate the effects of chronic administration of desimipramine (DMI) after 2, 7 or 20 mg/kg per day, administered by osmotic minipumps, on electrocortical activity and beta-adrenergic receptors in rat brain. Rats receiving DMI chronically show a dose- and time-dependent increase of electrocortical activity above 15 Hz as well as a dose- and time-dependent decrease below 15 Hz. Already after 3 days of treatment a clear effect on the electrocorticogram (ECoG) was seen. The maximal change in the ECoG was reached at the end of the study, after 24 days of treatment. After acute treatment (20 and 45 minutes after 2, 4 or 10 mg/kg i.p.) with DMI, a decrease of electrocortical activity is seen above 15 Hz. Thus the effect of acute DMI treatment on the ECoG is different from that of chronic treatment. In the same group of rats the effect of chronic DMI treatment on the beta-adrenergic receptor number was determined 24 hours after the last ECoG recording. The number of beta-adrenergic receptors was dose dependently reduced in the DMI-treated rats as determined by [3H]-dihydroalprenolol binding. There was no change in affinity (KD) of the ligand for the beta-receptor. This finding was corroborated by a decrease in the functional activity of the beta-adrenergic receptors, as determined by isoprenaline stimulated efflux of cyclic-AMP in cortex slices. These data indicate that chronic treatment with DMI, resulting in a down-regulation of the cortical beta-adrenergic system, is paralleled by pronounced effects on the ECoG of rats. The different ECoG profiles after chronic DMI treatment compared with acute treatment suggest that adaptive changes in the electrical brain activity continually develop during the chronic treatment with this antidepressant drug.


Subject(s)
Brain/drug effects , Desipramine/pharmacology , Receptors, Adrenergic, beta/drug effects , Animals , Brain/physiology , Electroencephalography , Electrophysiology , Male , Rats , Rats, Inbred Strains , Receptors, Adrenergic, beta/physiology
20.
J Med Chem ; 31(10): 1934-40, 1988 Oct.
Article in English | MEDLINE | ID: mdl-2902226

ABSTRACT

A series of 2-phenylpyrrole Mannich bases was synthesized and screened in pharmacological models for antipsychotic activity and extrapyramidal effects. Structure modifications of 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (1), the prototype of a new class of sodium-independent atypical dopamine D-2 antagonists, resulted in 2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-5-(4-fluorophenyl)pyrrole (15), which was an even more potent and selective D-2 antagonist than the parent compound. The excellent oral activity in the apomorphine-induced climbing behavior and the conditioned avoidance response tests and the absence of catalepsy make this compound particularly promising as a potential antipsychotic with a low propensity to induce acute extrapyramidal side effects.


Subject(s)
Antipsychotic Agents/chemical synthesis , Benzamides/pharmacology , Pyrroles/chemical synthesis , Animals , Apomorphine/pharmacology , Avoidance Learning/drug effects , Chemical Phenomena , Chemistry, Physical , Conditioning, Classical/drug effects , Corpus Striatum/metabolism , Dioxanes/metabolism , Mice , Rats , Spiperone/metabolism
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