Imipramine counteracts corticosterone-induced alterations in the effects of the activation of 5-HT(7) receptors in rat hippocampus.

Using extracellular recording we studied changes in the reactivity of rat hippocampal slices to an agonist of the 5-HT(7) receptor, 5-carboxamidotryptamine (5-CT; 0.025-1 microM), induced by an earlier treatment of animals with corticosterone. Spontaneous bursting activity was recorded in ex vivo slices incubated in the presence of 2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635; 2 microM), an antagonist of the 5-HT(1A) receptor, in the medium devoid of Mg2+ ions. Saturation binding assays were performed using [(3)H]-(2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), a specific antagonist of the 5-HT(7) receptor. Repetitive, but not single, corticosterone administration lasting 7 and 21 days, resulted in an enhancement of the effect related to the 5-HT(7) receptor activation without changes in its binding properties. In a separate set of experiments rats were treated with corticosterone for 3 weeks and additionally with imipramine, beginning on the eighth day of corticosterone administration. In the corticosterone plus imipramine group the excitatory effect of 5-CT was weaker than in the corticosterone group, indicating that corticosterone-induced functional modifications in the reactivity of the 5-HT(7) receptor were reversed and further weakened by imipramine treatment. This effect was accompanied by a reduction in the density of [3H]-SB 269970 binding sites. Thus, imipramine treatment counteracts the corticosterone-induced increase in the reactivity of the hippocampal circuitry to the activation of the 5-HT(7) receptor.

Synthesis, anticonvulsant activity and 5-HT1A, 5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-alkyl] derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione.

The synthesis, physicochemical and pharmacological properties of new N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane- (8a-c, 10a-d) and [4.5]decane-1,3-dione (9a-c, 11a-d) derivatives were described. The antiepileptic effects of those compounds were examined by a maximal electroshock (MES) and a pentylenetetrazole (sc. PTZ) tests, and their neurotoxicity was determined using a rota-rod test. Compounds 8c, 9c, 10c, d, 11c, d with a CF(3) group at the 3-position of the 4-arylpiperazine fragment exhibited anti-seizure properties in the MES model; in contrast, their 2-CH(3) and 2-OCH(3) analogues were inactive in both the tests used. Moreover, since the investigated compounds belong to the class of long-chain arylpiperazines, their serotonin 5-HT(1A) and 5-HT(2A) receptor affinity was determined. The relationship between the length of alkylene spacer and 5-HT(1A)/5-HT(2A) receptor activity was observed. Compounds with an ethylene and a propylene bridge (10a-d and 11a-d) were 3-80-fold more potent (K(i) ranged from 3.1 to 94 nM for 5-HT(1A) and 32-465 nM for 5-HT(2A)) than their methylene analogues (8a-c and 9a-c; K(i) ranged from 81 to 370 nM for 5-HT(1A) and 126-1370 nM for 5-HT(2A)). The highest 5-HT(1A) receptor affinity was displayed by 2-OCH(3) and 3-CF(3) phenyl derivatives (10b, 11b: K(i)=6.8 and 5.7 nM, respectively, and 10c, 11c: K(i)=6.0 and 3.1 nM, respectively), while in the case of 5-HT(2A) receptor the highest affinity was observed for the 3-CF(3) phenyl derivatives 10c, d, 11c, d (K(i) ranged from 32 to 86 nM).

Synthesis, 5-HT1A and 5-HT2A receptor activity of new 1-phenylpiperazinylpropyl derivatives with arylalkyl substituents in position 7 of purine-2,6-dione.

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.

Arylpiperazine derivatives of 3-propyl-beta-tetralonohydantoin as new 5-HT1A and 5-HT2A receptor ligands.

A series of new analogues of 3-[3-(4-arylpiperazinyl)-propyl]-cyclo-hexane-1',5-spirohydantoin (2), with aromatic ring fused in amide moiety (4-9) were synthesized and evaluated for affinity at 5-HTIA and 5-HT2A receptors. The influence of the substitution mode in the phenyl ring of phenylpiperazine moiety on the affinity for both receptors has been discussed. The most potent 5-HTIA (9, Ki = 53 nM) and 5-HT2A (4, 6, 8 and 9; Ki = 14-76 nM) ligands were evaluated in in vivo tests. The obtained results indicate that all in vivo tested compounds showed pharmacological profile of 5-HT2A antagonists. Additionally, a m-CF3 derivative (9), behaved like a partial agonist (agonist of pre- and antagonist of postsynaptic) of 5-HTIA receptors and may offer a new lead for the development of potential psychotropic agents.

Influence of the aliphatic spacer length on the 5-HT1A receptor activity of new arylpiperazines with an indazole system.

Novel arylpiperazines (1a, 1c, 2a and 2c), containing a terminal 1- or 2-indazolyl fragment and a di- or tetramethylene aliphatic spacer, were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. All those compounds showed a potent affinity for 5-HT1A receptors (Ki = 5-16 nM) and were evaluated for an intrinsic activity at those receptors. In order to determine a 5-HT1A agonistic effect of the investigated compounds, their ability to induce a lower lip retraction in rats and a behavioral syndrome (flat body posture and forepaw treading) in reserpinized rats were tested, whereas their 5-HT1A antagonistic activity was assessed via inhibition of those symptoms produced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT). The effect of spacer length on the 5-HT1A activity of the tested compounds was discussed in comparison with that of the three-methylene analogs (1b and 2b) described earlier. Both dimethylene derivatives (la and 2a) were characterized as weak postsynaptic 5-HT1A receptor antagonists. Compounds 1c (1-indazolyl analog) and 2c (2-indazolyl analog) with a tetramethylene aliphatic chain were classified as a postsynaptic 5-HT1A antagonist and a partial 5-HT1A agonist, respectively. Furthermore, the latter showed a moderate anxiolytic-like effect (conflict drinking Vogel's test in rats) and a weak antidepressant-like activity (forced swimming Porsolt's test in rats).

Structure-activity relationship studies of CNS agents. Part 38. Novel 1,4-benzoxazin-3(4H)-one, 1,2-benzoxazolin-3-one and 1,3-benzoxazolin-2,4-dione arylpiperazine derivatives with different 5-HT1A and antagonistic 5-HT2A activities.

New 1-arylpiperazine (series d-f) and 1,2,3,4-tetrahydroisoquinoline (series g) derivatives of 1,4-benzoxazin-3(4H)-one 1, 1,2-benzoxazolin-3-one 2, and 1,3-benzoxazolin-2,4-dione 3 with an n-butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5-HT1A and 5-HT2A receptors in comparison with trimethylene analogues (a, bc). 5-HT1A receptor binding constants of derivatives 1d-g, 2d-f, and 3d-f were very high (Ki = 1.25-54 nM), and 5-HT2A affinities were maintained at a similar, high level (Ki = 27-85 nM) for series d and e, and moderate (Ki = 246-495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5-HT1A/5-HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5-HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5-HT2A binding constants in comparison with trimethylene analogues. As shown by X-ray crystallography, this phenomenon may be attributed to the position of non-carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e-g, 2d-f, and 3f behaved like typical postsynaptic 5-HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5-HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5-HT1A antagonist.

1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands.

Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the terminal amide substituent was a crucial parameter which determined 5-HT1A receptor affinities of the tested compounds, while the in vivo activity seemed to depend on both the R-volume and the length of a hydrocarbon chain. It was demonstrated that the most active ligands behaved like agonists or partial agonists at postsynaptic 5-HT1A receptors.

A search for new 5-HT1A/5-HT2A receptor ligands. In vitro and in vivo studies of 1-[omega-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones.

A series of 1-¿omega-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2-14 was synthesized in order to obtain ligands with a dual 5-HT1A/5-HT2A activity. The majority of those compounds (2-5, 7, 10-13) exhibited a high 5-HT1A (Ki = 2-44 nM) and/or 5-HT2A affinity (Ki = 51 and 39 for 5 and 7, respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these effects evoked by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT1A receptors. The 5-HT2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-¿3-[4-(3-chlorophenyl)-1-piperazinyl]propyl¿-6-fluoroindolin-2(1 H)-one (5) and 1-¿3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl¿indolin-2(1H)-one (7), demonstrated a high 5-HT1A/5-HT2A affinity and an in vivo antagonistic activity towards both receptor subtypes.

1,4-Benzoxazin-3(4H)-one derivatives and related compounds as 5-HT1A and 5-HT2A receptor ligands; the effect of the terminal amide fragment on the 5-HT1A/5-HT2A affinity and functional activity.

A number of new 1-phenyl- (a), 1-(3-chlorophenyl)- (b) and 1-(2-methoxyphenyl)- (c) piperazine derivatives containing 1,4-benzoxazin-3(4H)-one (2-4), 2,4-benzoxazin-3-(4H)-one (5), 1,2-benzoxazolin-3-one (6) and 1,3-benzoxazolin-2,4-dione (7) were synthesized. Radioligand binding measurements showed that the majority of compounds had a distinct affinity for 5-HT1A (3a, 6a, 2-5b, 6c; Ki = 7.5-81 nM) and/or 5-HT2A (2b, 5-7a,b; Ki = 18-69 nM) receptors. Structure-Activity Relationship (SAR) studies revealed structural features which seem to favour the binding to either or both of these two receptor subtypes. For evaluation of the functional in vivo profile of the most potent 5-HT1A (5b, 6b) and/or 5-HT2A (5-7b) ligands, the following tests were used: the 8-OH-DPAT-induced lower lip retraction (LLR) and behavioral syndrome in rats--for 5-HT1A receptor antagonistic activity, and the (+/-)DOI-induced head twitches in mice and the (+/-)DOI-induced discriminative stimulus properties in rats--for 5-HT2A receptor antagonistic properties. The obtained results show that compounds 5b and 6c behave like potent 5-HT1A antagonists, whereas 5b, 6b and 7b demonstrate 5-HT2A receptor antagonistic properties. None of the in vivo tested compounds, given alone, mimicked 8-OH-DPAT activity in those tests. It seems that derivative 5b, which has an equipotent 5-HT1A and 5-HT2A affinity and antagonistic properties at both these receptors, is a promising potential psychotropic substance.

5-HT1A and 5-HT2A receptor affinity and functional profile of some N-[3-(4-aryl-1-piperazinyl)propyl] derivatives of indolin-2(1H)-one, quinolin-2(1 H)-one and isoquinolin-1(2H)-one. Part 30: Structure-activity relationship studies of CNS agents.

A series of new 1-aryl-4-propylpiperazines containing the modified terminal amide fragment 9, 15-19, 21, 23 and 25 were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. All the compound were highly potent 5-HT1A receptor ligands with a diverse 5-HT2A receptor affinity. It was found that the 5-HT2A receptor affinity depends on the dipole moment and lipophilicity of amide moiety. Compound 9b was found to be a 5-HT2A receptor antagonist and a weak 5-HT1A receptor agonist.

3-(omega-Aminoalkyl)-5,5-dialkyl(or spirocycloalkyl-1',5-)hydantoins as new 5-HT1A and 5-HT2A receptor ligands.

A series of new 3-(omega-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT1A and 5-HT2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT1A and 5-HT2A receptors due to the presence of a 1-arylpiperazine fragment however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new selective 5-HT2A receptor ligands (Ki = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine (38) is a new, highly potent 5-HT1A receptor ligand (Ki = 0.51 nM) with a moderate affinity for 5-HT2A receptors (Ki = 213 nM).

8-[4-[2-(1,2,3,4-Tetrahydroisoquinolinyl]butyl-8-azaspiro[4.5]decane-7,9-dione: a new 5-HT1A receptor ligand with the same activity profile as buspirone.

A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro- [4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-Ht1A receptors.

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.

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.

Structure-activity relationship studies of CNS agents, Part 23: N-(3-phenylpropyl)- and N-[(E)-cinnamyl]-1,2,3,4-tetrahydroisoquinoline mimic 1-phenylpiperazine at 5-HT1A receptors.

The 5-HT1A receptor affinities and ionization constants of a set of 1-arylpiperazine (4) 1,2,3,4-tetrahydroisoquinoline (6), and -quinoline (7) containing N-(omega-arylalkyl) or N-(E)-cinnamyl substituents as well as two morpholine derivatives (8a, 8b) were determined. It was shown that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives were 5-HT1A ligands equipotentto 1-phenylpiperazine (4a) and 1,2,3,4,4a,5-hexahydropyrazino [1,2-a]indole (5). On the basis of molecular modelling studies it was also demonstrated that 6c, 6d and 8a mimicked very well the reference structures of 4a and its rigid analog 5. Another, more complex 1,2,3,4-tetrahydroisoquinoline derivative 3, which served as a model compound to confirm the previously reported 5-HT1A binding mode of derivatives 1a-d and 2, had the highest 5-HT1A affinity (Ki = 6.7 +/- 0.5 nM) of all the investigated compounds.

Structure-activity relationship studies of CNS agents, Part 22. A search for new trazodone-like antidepressants: synthesis and preliminary receptor binding studies.

New 1-phenyl- and 1-(3-chlorophenyl)piperazines containing a 4-[3-(heterocyclic)propyl] fragment were synthesized. It was found that of all the investigated compounds 11b (Ki = 13 +/- 2 nM) and 8b (Ki = 38 +/- 2 nM) were the most active 5-HT1A and 5-HT2A ligands, respectively. Several derivatives (3a, 4a, 8b, 11b, 12b, 13a, and 13b) were selected as good candidates for new, potential antidepressants on the basis of their 5-HT1A/5-HT2A receptor binding profiles.

Structure-activity relationship studies of CNS agents--XVII. Spiro[piperidine-4',1-(1,2,3,4-tetrahydro-beta-carboline)] as a probe defining the extended topographic model of 5-HT1A receptors.

Spiro[piperidine-4',1-(1,2,3,4-tetrahydro-beta-carboline)] (10), its derivatives 11-15 and its analogs 16 and 17 were examined as ligands of serotonin 5-HT1A receptors. It was shown that compounds 12 and 14 had essentially the same 5-HT1A affinity as 1-phenylpiperazine and its rigid analog 7, whereas there were substantial differences in the steric arrangement of their crucial pharmacophores, i.e. aromatic and protonation centers. On the basis of the existing models and using the (+)-LSD structure as a template, a new, extended three-point topographic model of 5-HT1A receptors has been proposed.

Structure-activity relationship studies of CNS agents, XIX: Quantitative analysis of the alkyl chain effects on the 5-HT1A and 5-HT2 receptor affinities of 4-alkyl-1-arylpiperazines and their analogs.

The 5-HT1A and 5-HT2 receptor affinity of a set of 44 N-alkylated 1-aryl-piperazines and their analogs has been analyzed: the n-hexyl derivatives were the most potent and the most selective 5-HT1A ligands of all the investigated N-alkyl homologues. The alkyl chain may stabilize the 5-HT1A receptor-ligand complex by hydrophobic forces. A set of the alkyl substituent contributions (CHT1A) for prediction of the 5-HT1A affinity of N-alkyl derivatives of 1-arylpiperazines and related compounds have been defined on the basis of the Free-Wilson analysis.

Structure-activity relationship studies of CNS agents. Part 14: Structural requirements for the 5-HT1A and 5-HT2A receptor selectivity of simple 1-(2-pyrimidinyl)piperazine derivatives.

The 5-HT1A and 5-HT2A receptor affinity of model 1-(2-pyrimidinyl)-piperazine derivatives 15-21 and 23-32 has been determined. 2-(N-Methylpiperazino)-4,6-di(2-thienyl)pyrimidine 26 is a new, highly active and selective 5-HT2A receptor ligand. The topography of a molecule and the stereoelectronic effects of the thiophene rings are the major factors responsible for the high affinity and selectivity of 26 towards 5-HT2A sites.