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.

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.

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).

On the bioactive conformation of NAN-190 (1) and MP3022 (2), 5-HT(1A) receptor antagonists.

Structural modifications of 1, a postsynaptic 5-HT(1A) receptor antagonist, provided its flexible (8, 12) and rigid (7, 9, 11, 13) analogues. Compounds 7, 8, 9, and 11 showed high 5-HT(1A) receptor affinity (K(i) = 4-72 nM). They acted as 5-HT(1A) postsynaptic receptor antagonists, since, like 1, they inhibited the behavioral syndrome, i.e., flat body posture (FBP) and forepaw treading (FT), in reserpine-pretreated rats as well as the lower lip retraction (LLR) in rats, both induced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT(1A) receptor agonist. Compound 12, which demonstrated high 5-HT(1A) receptor affinity (K(i) = 50 nM), revealed properties of a partial 5-HT(1A) receptor agonist: it induced LLR and, at the same time, inhibited FT in rats. Compound 13 (K(i) = 1600 nM) was not tested in a behavioral study. Restriction of the conformational freedom in 2, a full 5-HT(1A) receptor antagonist, yielded compound 14 with high 5-HT(1A) receptor affinity (K(i) = 47 nM) and partial agonist properties at postsynaptic 5-HT(1A) receptors in the above tests in vivo; i.e., it induced LLR and inhibited FBP and FT in rats. New constrained analogues of 1 and 2 (compounds 7 and 14, respectively) were also synthesized to recognize a bioactive conformation of those 5-HT(1A) receptor antagonists. On the basis of in vitro and in vivo investigations, binding and functional properties of compound 7 were found to reflect those of 1 at 5-HT(1A) receptors. On the other hand, compound 14, a rigid analogue of 2, showed a different activity in vivo in comparison with the parent compound. PM3 and MM calculations revealed the existence of three low-energy conformers of 7 and six of 14, all of them belonging to the extended family of conformations. The optimized structures of both analogues had a different angle between aromatic planes of terminal fragments; moreover, the heteroaromatic system of those molecules occupied various space regions. Our present study provides support to the hypothesis that the bioactive conformation of 1, responsible for its postsynaptic 5-HT(1A) receptor antagonism, is an extended linear structure represented by 7.

Effect of the amide fragment on 5-HT1A receptor activity of some analogs of MP 3022.

A new set (3-11) of analogs of MP 3022 (1) containing the amide bond inserted into the intermediate chain linking the terminal heteroaromatic and 1-(2-methoxyphenyl)piperazine moieties were prepared and their 5-HT1A and 5-HT2A receptor affinities were determined. Only compounds with trimethylene chain between amide and arylpiperazine fragments (5a, 5b, 7a, 7b and 11) showed satisfactory affinity for 5-HT1A receptor (Ki = 42-87 nM) and high 5-HT2A/5-HT1A selectivity. The new 5-HT1A receptor ligands were investigated in vivo to determine their 5-HT1A agonistic or antagonistic properties. Compounds 7a and 7b with terminal indazole fragment as well as 11 with phenyl substituent behaved like weak 5-HT1A receptor antagonists. The structure-affinity relationship studies in this series of compounds revealed that the amide group along with the terminal aromatic fragments contributed to interaction with 5-HT1A receptor sites, whereas in vivo results indicated that introduction of the amide group into presented arylpiperazine structures was not a profitable modification for their 5-HT1A functional activity.

Some pharmacological properties of new analogs of MP 3022, the 5-HT1A receptor antagonist.

Two new analogs of full 5-HT1A receptor antagonist 4-[3-(1-benzotriazolyl)propyl]-1-(2-methoxyphenyl)piperazine (MP 3022; 1) containing di- (5) or tetramethylene- (6) spacer were synthesized. In the radioligand binding studies, compounds 5 and 6 showed high 5-HT1A (Ki = 14.7 nM and 11.8 nM, respectively) and low 5-HT2 receptor affinity (Ki = 2,696 nM and 389.2 nM, respectively). In behavioral studies both compounds behaved like postsynaptic 5-HT1A receptor antagonists as they reduced lower lip retraction and behavioral syndrome induced by 8-OH-DPAT (5-HT1A receptor agonist) in rats, but 6 was more effective in these tests. Derivative 5 did not affect body temperature in mice, whereas 6 decreased it. Furthermore, 5 did not change hypothermia induced by 8-OH-DPAT, and 6-induced lowering of body temperature in mice was not antagonized by (S)-WAY 100135 (5-HT1A antagonist), so in that model 5 and 6 did not behave as antagonist or agonist, respectively, at presynaptic 5-HT1A receptors. Compound 6 was studied in behavioral tests used to predict a potential anxiolytic (conflict drinking test in rats) and antidepressant (forced swimming test in rats) activity. Diazepam and imipramine were used as reference drugs. Compound 6 significantly increased the number of shocks accepted in water-deprived rats in conflict drinking test and shortened the immobility time in forced swimming test in rats. The above findings indicate that new 5-HT1A postsynaptic antagonist 6 behaves like anxiolytic and antidepressant, but mechanisms of these properties of 6 remain unknown.

Effect of linking bridge modifications on the 5-HT1A receptor activity of some 4-(omega-benzotriazol-1-yl)alkyl-1-(2-methoxy-phenyl)piperazines.

A new series of arylpiperazines with two (2a-4a) and four (2c-4c) methylene spacers was synthesized. Compounds 2a, 2c, 3c, 4a and 4c were found to be 5-HT1A ligands (Ki = 4-88 nM). The most promising compound, 2c, bound with the highest affinity (Ki = 4 nM) at 5-HT1A sites. The results of in vivo experiments showed that compounds 2a-4a were inactive, while 2c-4c revealed a distinct antagonistic activity towards postsynaptic 5-HT1A receptors. The pharmacological profile of the tested compounds was discussed in comparison with that of the three methylene analogs b, described earlier.

Structure-activity relationship studies of CNS agents, Part 32: Effect of structural modifications in 1-arylpiperazine derivatives on alpha(1) -adrenoreceptor affinity.

The alpha(1)-adrenergic and 5-HT1A serotonergic receptor affinities of a series of 1-arylpiperazines are presented. The role of the spacer and the influence of the terminal substituents on the alpha(1)-adrenoreceptor affinity and the 5-HT1A/alpha(1) receptor selectivity are discussed.

Structure-activity relationship studies of CNS agents, Part 31: Analogs of MP 3022 with a different number of nitrogen atoms in the heteroaromatic fragment--new 5-HT1A receptor ligands.

Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines (3, 4a, 4b, 6-9, and 12-13) and 2-(n-propyl)-1,2,3,4-tetrahydroisoquinolines (5a, 5b, 11a, and 11b) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT1A/5-HT2A and alpha 1 receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT1A/5-HT2A/alpha 1 receptor ligands. Compounds 3, 4a, 4b, 7-9a with the highest affinity for 5-HT1A receptors (Ki = 4-54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8, and 9a behaved like weak antagonists of postsynaptic 5-HT1A receptors, 4b and 7 may be classified as potential partial 5-HT1A receptors, agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT1A receptor agonist.

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, 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 central nervous system agents. 13. 4-[3-(Benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)piperazine, a new putative 5-HT1A receptor antagonist, and its analogs.

A new set of 4-alkyl-1-(o-methoxyphenyl)piperazines containing a terminal benzotriazole fragment were synthesized, and their 5-HT1A and 5-HT2 affinity was determined. It was shown that the benzotriazole moiety contributes to both the 5-HT1A and 5-HT2 receptor affinity. It was demonstrated in several behavioral models that 4-[3-(benzotriazol-1- yl)propyl]-1-(2-methoxyphenyl)piperazine (11) is a new, potent presynaptic and postsynaptic 5-HT1A receptor antagonist. However, it is not selective for 5-HT1A versus alpha 1 receptors.

Structure-activity relationship studies of CNS agents. XII. 1-[4-(4-aryl-1-piperazinyl)butyl]-3,4-dihydro-2(1H)-quinolinones: new 5-HT1A, 5-HT2 and D2 ligands with a potential antipsychotic activity.

The synthesis of three 1-[4-(4-aryl-1-piperazinyl)butyl]-3,4-dihydro-2(1H)-quinolinones (5-7) was described and the receptor binding profile (5-HT1A, 5-HT2, alpha 1, D1, D2) was determined. It was found that m-chloro (5) and o-methoxy (6) derivatives are potent antagonists of the 5-HT1A, 5-HT2 and D2 receptors. It was shown that compound 6 resembles very well some atypical antipsychotics and may be considered as a novel agent of this class of drugs.

Structure-activity relationship studies of CNS agents. Part VIII. Bulk tolerance around the protonation center of 4-substituted 1-(3-chlorophenyl)piperazines at 5-HT1A and 5-HT2 receptors.

The effect of a steric hindrance around the protonation center of the model 4-substituted 1-(3-chlorophenyl)-piperazines 1-9 and 11-14 on their affinity for 5-HT1A and 5-HT2 receptor sites was investigated. Additional evidence for hydrophobic interactions between the N-4 hydrocarbon substituents and 5-HT1A receptors has been presented. However, the hydrophobic forces play a minor role in stabilization of the bioactive complex with 5-HT2 receptors. It has also been found that even bulky substituents around the protonation center of 1-aryl-piperazines are well tolerated at both 5-HT1A and 5-HT2 sites.