ABSTRACT
A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D(1), D(2), D(4)) and serotonin receptors (5-HT(2A), 5-HT(2B), 5-HT(2C)), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT(2A) receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)p iperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs.
Subject(s)
Antipsychotic Agents/chemical synthesis , Butyrophenones/chemical synthesis , Isoxazoles/chemical synthesis , Piperidines/chemical synthesis , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Binding, Competitive , Butyrophenones/chemistry , Butyrophenones/metabolism , Butyrophenones/pharmacology , Catalepsy/chemically induced , Cattle , Corpus Striatum/metabolism , Frontal Lobe/metabolism , Humans , In Vitro Techniques , Isoxazoles/chemistry , Isoxazoles/metabolism , Isoxazoles/pharmacology , Male , Mice , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2B , Receptor, Serotonin, 5-HT2C , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D4 , Retina/metabolismABSTRACT
We describe practical and efficient routes for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using the Fischer indole synthesis or palladium-catalysed cyclization methodologies, as well as their affinities for D(2), 5-HT(2A) and 5-HT(2C) receptors, and their activity at the 5-HT(2B) receptor. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with a pK(i) (5-HT(2A)/D(2)) ratio of 1.28 show a potential antipsychotic profile according to Meltzer's classification.
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/metabolism , Butyrophenones/chemistry , Carbazoles/chemistry , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Carbazoles/chemical synthesis , Carbazoles/metabolism , Carbazoles/pharmacology , Cattle , Cell Membrane/metabolism , Choroid Plexus/metabolism , Frontal Lobe/metabolism , Isoxazoles/chemical synthesis , Isoxazoles/metabolism , Isoxazoles/pharmacology , Male , Piperazines/chemical synthesis , Piperazines/metabolism , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/pharmacologyABSTRACT
A series of novel conformationally restricted butyrophenones (2-(aminoethyl)- and 3-(aminomethyl)thieno- or benzocycloalkanones bearing (6-fluorobenzisoxazolyl)piperidine, (p-fluorobenzoyl)piperidine, (o-methoxyphenyl)piperazine, or linear butyrophenone fragments) were prepared and evaluated as atypical antipsychotic agents by in vitro assays of affinity for dopamine receptors (D(1), D(2)) and serotonin receptors (5-HT(2A), 5-HT(2C)) and by in vivo assays of antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cycloalkanone structure. As a group, compounds with a benzisoxazolyl fragment had the highest 5-HT(2A) activities, followed by the benzoylpiperidine derivatives; in general, alpha-substituted cycloalkanone derivatives were more active than the corresponding beta-substituted congeners. CoMFA (comparative molecular field analysis) and docking studies showed electrostatic, steric, and lipophilic determinants of 5-HT(2A) and D(2) affinities and 5-HT(2A)/D(2) selectivity. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4H-5, 6-dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisox azol-3 -yl)piperidine (23b, QF 0510B), N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (24b, QF 0610B), and N-[(7-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-6-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (29b, QF 0902B) suggest that they may be effective antipsychotic drugs with low propensity to induce extrapyramidal side effects.
Subject(s)
Antipsychotic Agents/chemical synthesis , Dopamine Agents/chemical synthesis , Isoxazoles/chemical synthesis , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Serotonin Agents/chemical synthesis , Thiophenes/chemical synthesis , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Brain/metabolism , Catalepsy/chemically induced , Cattle , Dopamine Agents/chemistry , Dopamine Agents/metabolism , Dopamine Agents/pharmacology , In Vitro Techniques , Isoxazoles/chemistry , Isoxazoles/metabolism , Isoxazoles/pharmacology , Male , Mice , Models, Molecular , Motor Activity/drug effects , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2C , Serotonin Agents/chemistry , Serotonin Agents/metabolism , Serotonin Agents/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/metabolism , Thiophenes/pharmacologyABSTRACT
We describe a practical and efficient route for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using an effective Fisher indole methodology. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with pKi (5-HT2A/D2) ratio of 1.28 show an antipsychotic profile according to Meltzer's classification.
Subject(s)
Antipsychotic Agents/chemical synthesis , Butyrophenones/pharmacology , Receptors, Dopamine D2/drug effects , Receptors, Serotonin/drug effects , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Butyrophenones/chemical synthesis , Receptor, Serotonin, 5-HT2AABSTRACT
Starting from benzo- or thienocycloalkaneacetic acids, we have prepared a series of 1-(3-p-fluorobenzoylpropyl)-4-(1-oxo-benzo- or thienocycloalkyl-2-ethyl)piperazines 8a-e containing both semirigid and linear butyrophenones pharmacophores. The affinities of these compounds for dopamine (D2) and 5-hydroxytryptamine (5-HT2A) receptors were evaluated in vitro in receptor-binding assays and in functional experiments. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds and assessing potential induction of extrapyramidal symptoms; ratio values > or = 1.12 (Meltzer's ratio) are predictive of an atypical antipsychotic profile. The new molecules had a ratio in the range of 0.96-1.11 while haloperidol showed a ratio of 0.93. The 2-piperazinoethyl thiotetralone derivative 8d (QF 0506B) with a ratio of 1.11 was the most active compound.