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.

The novel buspirone analogue, 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)[butyl]-8-azaspiro [4.5 ]decane-7,9-dione, with anxiolytic-like and antidepressant-like effects in rats.

In the conflict drinking test, used as a model to examine anxiolytic-like activity, the novel buspirone analogue 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl)-8-azaspiro[ 4.5]decane-7,9-dione (MM199) (0.62-2.5 mg/kg) and buspirone (0.62-5 mg/kg), significantly increased the punished drinking in water-deprived rats, without affecting water consumption or perception of the stimulus. The anticonflict activity of MM199 (1.25 mg/kg) was blocked by (S)-WAY 100135 (20 mg/kg), a 5-hydroxytrypatmine1A (5-HT1A) receptor antagonist. In the forced swimming test, used as a model to examine the antidepressant-like activity, MM199 (5-20 mg/kg) reduced the immobility time, while buspirone (5-20 mg/kg) had no such effect. The reduced immobility induced by MM199 (20 mg/kg) was antagonized by (S)-WAY100135 (10 mg/kg). The above findings suggest that MM199 possesses potent anxiolytic- and antidepressant-like properties which are mediated by activation of 5-HT1A receptors.

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.

Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist.

Using the forced swimming test in rats (Porsolt test), we examined the antidepressant-like activity of 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at strychnine-insensitive glycine receptors associated with the N-methyl-D-aspartate (NMDA) receptor complex, and of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive NMDA receptor antagonist, after their intraperitoneal (i.p.) and intrahippocampal (i.hp.) administration. ACPC (200-400 mg/kg) and CGP 37849 (0.625-5 mg/kg), administered i.p., produced a dose-dependent and significant reduction of the immobility time in the forced swimming test. A similar effect was also observed in i.hp. administration of ACPC (10 and 30 micrograms) and CGP 37849 (0.03 and 0.1 micrograms). Imipramine, used as a reference drug, significantly shortened the immobility time after both i.p. (30 and 40 mg/kg) and i.hp (0.1 and 0.3 micrograms) administration. The compounds studied, administered in doses effective in the forced swimming test, did not change the exploratory activity of the rats, evaluated by an open field test. The present results indicate that, like imipramine, ACPC and CGP 37849 exhibit an antidepressant-like activity in the forced swimming test in rats; moreover, they seem to show the hippocampus may be one of the neuroanatomical sites involved in this effect.

Effect of glycine on antidepressant- and anxiolytic-like action of 1-aminocyclopropanecarboxylic acid (ACPC) in rats.

Glycine (800 mg/kg ip) abolished the antimmobility effect of 1-aminocyclopropanecarboxylic acid (ACPC) given both ip (400 mg/kg) and ihp (30 micrograms) in the forced swimming test in rats, but did not affect the anticonflict activity of ACPC (200 mg/kg ip or 10 micrograms ihp) in the conflict drinking test.

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.

Anticonflict effects of a competitive NMDA receptor antagonist and a partial agonist at strychnine-insensitive glycine receptors.

Using the conflict drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist and 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at strychnine-insensitive glycine receptors associated with the NMDA receptor complex, after their intraperitoneal (i.p.) and intrahippocampal (IHP) administration. CGP 37849, administered in doses of 1.25-5 mg/kg i.p., produced an anticonflict effect in a dose-dependent manner, but was inactive when injected in doses of 0.01-0.1 micrograms IHP. At the same time, when administered in higher doses (10 mg/kg i.p. or 0.3 micrograms IHP), that drug induced motor impairment. On the other hand, ACPC exhibited an anxiolytic-like activity after both i.p. (100-200 mg/kg) and IHP (3-30 micrograms) administration. These results, as well as the literature data on the lack of motor-impairing effects of ACPC, indicate that the latter drug seems to be more advantageous than CGP 37849 as a potential therapeutic agent in the treatment of anxiety disorders. Furthermore, they also show that the hippocampus may be one of the neuroanatomical sites of the anxiolytic-like effect of ACPC, but not of CGP 37849.

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.

Involvement of 5-HT2C receptors in the m-CPP-induced antinociception in mice.

Effects of the non-selective 5-hydroxytryptamine (5-HT) receptor agonist m-chlorophenylpiperazine (m-CPP) on the nociceptive responsiveness in a hot plate and tail flick tests were examined in mice. Intraperitoneal administration of m-CPP (1-10 mg/kg) produced a dose-dependent antinociception in both those tests; the effect of m-CPP in the hot plate test was stronger. The antinociceptive effect of m-CPP in either test was abolished by pretreatment with mesulergine (2 mg/kg), ritanserin (1-2 mg/kg), 5-HT2A/5-HT2C receptor antagonists, and metergoline (0.5-2 mg/kg), a non-selective 5-HT receptor antagonist. On the other hand, spiperone (0.25-0.5 mg/kg), a dopamine, 5-HT1A and 5-HT2A receptor antagonist; pindolol (4-8 mg/kg), a beta-adrenoceptor, 5-HT1A and 5-HT1B receptor antagonist and zacopride (0.1-1 mg/kg) a 5-HT3 receptor antagonist, did not affect the analgesia induced by m-CPP. Neither of the drugs used as putative receptor antagonists changed the nociceptive responsiveness in mice. The obtained results suggest that the analgesia induced by m-CPP is mediated by 5-HT2C receptors.

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.

Central effects of SL 82.0715, an antagonist of polyamine site of the NMDA receptor complex.

Central effects of SL 82.0715, an antagonist of polyamine site of the NMDA receptor complex, was studied in male Albino-Swiss mice. SL 82.0715, in doses which given alone were inactive in electroshock-induced seizures, potentiated the anticonvulsant effects of CGP 37849. In normal mice, SL 82.0715 decreased the spontaneous locomotor activity, did not affect the locomotor hyperactivity induced by MK-801 and attenuated CGP 37849-induced locomotor hyperactivity. The D-amphetamine locomotor hyperactivity was also antagonized by SL 82.0715. SL 82.0715 did not significantly change the locomotor activity in monoamine-depleted mice (treated with reserpine + alpha-methyl-p-tyrosine). When administered together with clonidine, SL 82.0715 increased the locomotor activity in monoamine-depleted mice but this effect did not reach the level of statistical significance. SL 82.0715 did not change the locomotor activity induced by joint administration of clonidine and MK-801 or clonidine and CGP 37849, in monoamine-depleted mice. The locomotor hyperactivity evoked by L-DOPA (given jointly with benserazide) was not changed by SL 82.0715. SL 82.0715 had no effect on fluphenazine- and haloperidol-induced catalepsy in mice. CGP 37849 attenuated catalepsy induced by haloperidol; that effect was not changed by SL 82.075. The studied compound did not affect the immobility time and had no effect on the action of MK-801 or CGP 37849 in the forced swimming test. The obtained results indicate that SL 82.0715 has a different pharmacological profile than other NMDA antagonists (at least MK-801 and CGP 37849). SL 82.0715 does not increase behavioral actions of MK-801 and CGP 37849, potentiating anticonvulsant effect of CGP 37849 only.

Investigations on the synthesis and properties of some N-heteroarylpiperazinylalkyl derivatives of imides of 3,4-pyridinedicarboxylic acids.

The synthesis of N-heteroarylpiperazinylalkyl derivatives of imides of 3,4-pyridinedicarboxylic acids is described. In pharmacological screening some of the obtained compounds proved to be pharmacologically active.

The effect of repeated treatment with oxaprotiline enantiomers on central 5-HT receptor subpopulations.

The effect of repeated administration of (+)-OXA (a noradrenaline (NA) uptake inhibitor) and (-)-OXA (devoid of an effect on the NA uptake, but a clinically active antidepressant drug) on central 5-HT receptor subpopulations was studied. (-)-OXA given repeatedly, but not acutely, attenuated the 8-OH-DPAT-induced hypothermia in mice. (+)-OXA administered acutely, as well as repeatedly, was inactive in that test. The 8-OH-DPAT-induced syndrome in rats was attenuated by both OXA isomers administered either acutely or repeatedly. The hypothermia induced by m-CPP in mice was attenuated by single-dose administration of (+)-OXA and (-)-OXA; when given repeatedly, (+)-OXA increased the action of m-CPP. (-)-OXA administered repeatedly was inactive in that test. Either single or repeated administration of (+)-OXA had practically no effect on the depression of exploratory activity induced by m-CPP. (-)-OXA administered acutely or repeatedly attenuated the effect of m-CPP in the same manner. Acute, but not chronic, administration of (-)-OXA reduced the number of head-twitch episodes induced by 5-HTP in mice. Repeated, but not acute, treatment with (+)-OXA attenuated the effect of 5-HTP. The obtained results indicate that (+)-OXA administered repeatedly increases the reactivity of 5-HT1B receptors, decreases the reactivity of 5-HT2 receptors, and has no effect on the reactivity of 5-HT1A- (pre- and postsynaptic) and 5-HT1C-receptors. (-)-OXA given repeatedly decreases the reactivity of presynaptic 5-HT1A receptors and has no influence on the reactivity of postsynaptic 5-HT1A-, 5-HT1B-, 5-HT1C- and 5-HT2-receptors.