Abstract:The 3-and 4benzoylpiperidines and 3-benzoylpyrrolidines were prepared by the reaction of l-acetylisonipecotoyl or 1-acetylnipecotoyl chloride with a substituted aromatic compound under Friedel-Crafts conditions or by treatment of the cyanopiperidines and pyrrolidines with an arylmagnesium halide. Alkylation gave the I-substituted compounds which were evaluated as CNS depressants. The I-substituted 4(p-fluorobenzoyl)piperidines were the most active compounds, several of which were more potent than chlorpromazin… Show more
“…Both compounds retain the 5-HT2 affinity and selectivity of 9. The ether counterpart of amide 12 (i.e., 15), and its reverse amide 16, both behaved like 12. In each of these instances however, 5-HT2 affinity is still 30-100 times less than that of spiperone.…”
DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5-HT1C/2 serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT1C- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT1C- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT1A serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT1C sites and (b) it has been used as a "5-HT2-selective" antagonist. Because spiperone is a behaviorally disruptive agent, it is not suitable for use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure-affinity investigation was conducted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lack the disruptive actions of spiperone. Various modifications of the spiperone molecule were examined, but most resulted in decreased 5-HT2 affinity or in loss of selectivity. One compound, 8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]de can-4-on e (26), was shown to bind at 5-HT2 sites with high affinity (Ki = 2 nM) and > 2,000-fold selectivity versus 5-HT1C sites. In tests of stimulus antagonism using rats trained to discriminate 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonist (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated with spiperone. As such, (a) it would appear that the DOM stimulus is primarily a 5-HT2-mediated, and not 5-HT1C-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.
“…Both compounds retain the 5-HT2 affinity and selectivity of 9. The ether counterpart of amide 12 (i.e., 15), and its reverse amide 16, both behaved like 12. In each of these instances however, 5-HT2 affinity is still 30-100 times less than that of spiperone.…”
DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5-HT1C/2 serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT1C- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT1C- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT1A serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT1C sites and (b) it has been used as a "5-HT2-selective" antagonist. Because spiperone is a behaviorally disruptive agent, it is not suitable for use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure-affinity investigation was conducted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lack the disruptive actions of spiperone. Various modifications of the spiperone molecule were examined, but most resulted in decreased 5-HT2 affinity or in loss of selectivity. One compound, 8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]de can-4-on e (26), was shown to bind at 5-HT2 sites with high affinity (Ki = 2 nM) and > 2,000-fold selectivity versus 5-HT1C sites. In tests of stimulus antagonism using rats trained to discriminate 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonist (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated with spiperone. As such, (a) it would appear that the DOM stimulus is primarily a 5-HT2-mediated, and not 5-HT1C-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.
“…Both Ia,e have two butyrophenone pharmacophores: the common semirigid 3-(aminomethyl)tetralone fragment and either a flexible linear butyrophenone moiety linked to the cycloalkanone by a piperazine bridge (Ie) or a 4-(p-fluorobenzoyl)piperidine moiety in which carbons 2-4 of the butyrophenone form part of a six-membered ring (Ia). As early as 1970, this latter structure was described as an antipsychotic pharmacophore of similar potency to linear butyrophenones, 39 and a SAR study of ketanserin analogues has suggested that the benzoyl carbonyl (present in both Ia,e) may play a prominent role in anchoring or orienting these compounds at receptor 5-HT 2 . 40 We subsequently extended our SAR study to the 2-(aminoethyl)benzocycloalkanones IIa,d-f, IIIa,d-f, and IVa, [41][42][43] the 5-(aminoethyl)-4,5,6,7-tetrahydroindol-4-ones Vd,f, 44 (butyrophenone homologues of the antipsychotic molindone), the 6-aminomethyl analogues VIa-f, 45,46 and the 2-(aminomethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-ones VIIa,b,f.…”
Section: Introductionmentioning
confidence: 99%
“…Both Ia , e have two butyrophenone pharmacophores: the common semirigid 3-(aminomethyl)tetralone fragment and either a flexible linear butyrophenone moiety linked to the cycloalkanone by a piperazine bridge ( Ie ) or a 4-( p -fluorobenzoyl)piperidine moiety in which carbons 2−4 of the butyrophenone form part of a six-membered ring ( Ia ). As early as 1970, this latter structure was described as an antipsychotic pharmacophore of similar potency to linear butyrophenones, and a SAR study of ketanserin analogues has suggested that the benzoyl carbonyl (present in both Ia , e ) may play a prominent role in anchoring or orienting these compounds at receptor 5-HT 2 2 3 NRR of Structures in Chart …”
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.
“…Esterification using thionyl chloride and methanol and then N-alkylation with benzylbromide under basic conditions afforded compound 6 , which after LAH reduction produced primary alcohol 7 . Swern oxidation of alcohol 7 yielded aldehyde 8 , which after condensation with 3-methoxyphenylmagnesium bromide gave compound 9 . Friedel−Crafts reaction of 9 in tert -butylbenzene yielded several products, from which we could isolate 10 , although in low yield.…”
SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonist of the delta-opioid receptor. In a previous report we had described the unique biological characteristics of this ligand and also a need for further structural evaluation.(6) To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeling studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the original piperazine scaffold (5 and 11). The biological activities of these compounds revealed an important participation of the scaffold in the ligand-receptor interaction. To further explore functional diversity on the scaffold, we have maintained the original piperazine ring and introduced four different functionalities at position 2 of the heterocyclic ring (15a-d; a = CH(2)-O-CH(2)-Ph; b = Me; c = CH(2)Ph; d = CH(2)OH). The biological activities observed for these compounds showed a very interesting trend in terms of the steric effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the delta-receptor was observed for 15c compared with 15b. This difference may be explained if we postulate that the bioactive conformation of these peptidomimetics is close to the minimal energy conformations calculated in our study. On the basis of these findings we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
