Showing papers by "ACADIA Pharmaceuticals Inc. published in 2000"

Iron-Mediated Synthetic Routes to Unsymmetrically Substituted, Sterically Congested Benzophenones

Abstract: A new synthetic route to unsymmetrically substituted benzophenones, relying upon iron-mediated reactions in all of the key steps, is described. The key buiding block, η6-2-chloro-carbomethoxybenzene-η5-cyclopentadienyl iron hexafluorophosphate (4), is reacted with a variety of substituted phenols, providing diaryl ether complexes (6). After hydrolysis of the ester functionalities, these complexes are subjected to Friedel−Crafts conditions. The efficiency of this intramolecular acylation reaction is very much dependent upon the substituents on the phenols. If these are appropriately chosen, xanthone complexes are isolated in fair to good yields. Regioselective ring-opening, using oxygen-nucleophiles, delivers substituted benzophenone complexes. After regioselective nucleophilic addition of cyanide ion, performed in the presence of DDQ, highly substituted benzophenones are isolated. To demonstrate the applicability of the new route, a formal synthesis of the benzophenone moiety of the protein kinase C inhib...

Derivatives of (R)-1,11-methyleneaporphine: synthesis, structure, and interactions with G-protein coupled receptors.

Abstract: The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.

Neuroactive steroids attenuate cocaine-induced sucrose intake in rats, but not cocaine-induced hyperactivity in mice.

Abstract: Rationale: Neuroactive steroids, including the potent anticonvulsants ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) and Co 2-1068 (3β-(4acetylphenyl)ethynyl-3α,21-dihydroxy-5β-20-one-21-hemisuccinate), have recently been shown to protect against cocaine-induced seizures. Objectives: The purpose of the present experiments was to determine whether ganaxolone and Co 2-1068 attenuate acute behavioral effects of cocaine unrelated to seizures. Methods: In the first experiment, the locomotor effects of Co 2-1068 (10–100 mg/ kg), pentobarbital (10–100 mg/kg) and haloperidol (0.03–0.3 mg/kg), alone or in combination with cocaine (5.6–30 mg/kg), were determined in mice. In the second experiment, the effects on sucrose intake of ganaxolone (4–16 mg/kg), Co 2-1068 (8–64 mg/kg), pentobarbital (4–32 mg/kg), and haloperidol (0.04–0.4 mg/kg), alone or in combination with cocaine (4–16 mg/kg), were determined in rats. Results: Cocaine caused a dose-related increase in locomotor activity in mice, whereas Co 2-1068, pentobarbital and haloperidol caused dose-related decreases. The dopamine antagonist haloperidol, at a dose that had no effect on activity by itself, but not Co 2-1068 or pentobarbital, attenuated the cocaine-induced increase in locomotor activity. Cocaine, ganaxolone, Co 2-1068, and haloperidol produced dose-related decreases in sucrose intake in rats; the effects of pentobarbital on sucrose intake were variable. As with locomotor effects, haloperidol attenuated the cocaine-induced decrease in sucrose intake. In addition, cocaine-induced decreases in sucrose intake were attenuated by ganaxolone and Co 2-1068. Pentobarbital had no statistically significant effect on the cocaine dose-response function. Conclusions: These results suggest that the interaction of neuroactive steroids with cocaine extends to pharmacologic actions beyond anticonvulsant efficacy, but that the blockade of behavioral effects of cocaine by neuroactive steroids does not apply to all acute behaviors.

Microwave-Assisted Solvent-Free Parallel Synthesis of Thioamides.

Abstract: Rapid parallel synthesis of thioamides is described. A library of amides, synthesised by mixing acyl chlorides and diamines, was transformed into the corresponding thioamides utilising Lawesson's reagent as the oxygen/sulphur exchange reagent. Purification by solid-phase extraction afforded the library members in adequate purities and yields.

Solid phase parallel synthesis of tertiary amines

Abstract: Described is method for preparing tertiary amines comprising sequential, exhaustive alkylation of a hydroxylamine derivative and cleavage of the O-N bond using the following steps: (a) reacting the hydroxylamine derivative with an alkylating agent or with a carbonyl compound to form an oxime intermediate; (b) reacting the oxime intermediate with a reducing agent to produce an alkylated derivative; (c) reacting the alkylated derivative with an alkylating agent or a carbonyl compound in the presence of a reducing agent to produce a dialkylated derivative; (d) reacting the dialkylated derivative with an alkylating agent to produce a quaternized derivative; (e) reacting the quaternized derivative with a reagent causing cleavage of the O-N bond to produce a tertiary amine.

Temporary in situ Aluminum and Zinc Tethering in Diels—Alder Reactions.

Abstract: (formula presented) Temporary tethering using aluminum or zinc in Diels-Alder reactions made possible the use of otherwise "noncompatible" combinations of dienes and dienophiles, resulting in the one-step formation of substituted cyclohexene 1,2-bis-methanols. Excellent regioselectivity and also significant stereoselectivity were obtained.