ABSTRACT
A potent sigma (sigma) receptor ligand was isolated from the culture broth of Streptomyces longispororuber #525. The active compound was identified to be (2R-trans)-2-butyl-5-heptylpyrrolidine by spectroscopic and chemical studies. The compound exhibited high affinity and selectivity for sigma receptors. The IC50 values toward sigma1, sigma2 and dopamine D2 receptors were 2.0, 22.7 and more than 40,000 nM, respectively. Its (2S-trans)- and (+/-)-cis-isomers, both synthesized, were also found to be high affinity sigma ligands.
Subject(s)
Pyrrolidines/metabolism , Receptors, sigma/metabolism , Streptomyces/metabolism , Animals , Fermentation , In Vitro Techniques , Ligands , Molecular Structure , Rats , Spectrum AnalysisABSTRACT
Cyclic imides bearing omega-(4-benzisothiazol-3-yl-1-piperazinyl)alkyl moieties were synthesized and tested for antipsychotic activity. The in vitro binding affinities of these compounds were examined for dopamine 2 (D2) and serotonin 2 (5-HT2) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis- cyclohexamedicarboximide (SM-9018), was found to be more potent and more selective in vivo than tiospirone in its antipsychotic activity. SM-9018 (17) is currently undergoing clinical evaluation as a selective antipsychotic agent.
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Succinimides/chemical synthesis , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Animals , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/psychology , Central Nervous System Depressants/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Haloperidol/pharmacology , In Vitro Techniques , Isoindoles , Mice , Motor Activity/drug effects , Neostriatum/drug effects , Neostriatum/metabolism , Psychotropic Drugs/pharmacology , Rats , Serotonin Antagonists/pharmacology , Spiro Compounds/pharmacology , Stereotyped Behavior/drug effects , Structure-Activity Relationship , Succinimides/pharmacologyABSTRACT
The antifungal activity of orally active SM-4470, (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazole-1-yl)-2-propanol hydrochloride, was compared with that of ketoconazole. SM-4470 showed twofold-higher activity than ketoconazole in the oral treatment of systemic infection with Candida albicans in mice. In addition, SM-4470 was effective against aspergillosis in mice, but ketoconazole was ineffective. The efficacy of SM-4470 was similar to that of ketoconazole in curing experimental candidal vaginitis in rats and trichophytosis in guinea pigs, although its serum concentrations in these animals were lower than those of ketoconazole. These data suggest that SM-4470 may be of value in the treatment of both systemic and superficial fungal infections in humans.
