Structure-activity relationship of trihexyphenidyl analogs with respect to the dopamine transporter in the on going search for a cocaine inhibitor.

A series of trihexyphenidyl (THP) analogs were used to search for a derivative that could serve as a cocaine inhibitor. A compound that blocks binding of the cocaine analog carboxyfluorotropane (CFT), allows dopamine uptake and exhibits low side effects could serve as a good candidate for that purpose. All analogs were tested for the extent to which they inhibit CFT binding, dopamine uptake and n-methyl scopolamine (NMS) binding. Several structure-function relationships emerged. Methylation/halogenation of THP's benzene ring enhanced the compound's ability to block CFT binding in comparison to its ability to block dopamine uptake (5a-e). Replacement of the cyclohexyl ring with a benzene ring tended to create compounds that had lower affinities to the dopamine transporter (7b compared to THP, 7d compared to 5h, 7c compared to 8c) and modification of THP's piperidine ring tended to enhance affinity to the dopamine transporter (5f-h, 8a, 8c). One analog (5f) that showed little muscarinic activity indicating that it would probably have few side effects was investigated for its effects as an in vivo cocaine inhibitor. However, it showed few antagonistic effects in vivo. Nevertheless, this work greatly elucidates the structure-function relationships required for potential cocaine inhibitors and so lays out promising directions for future research.

Anticholinergic agents. 4. Stereocontrolled synthesis of fluorinated acetylcholine antagonists; syntheses of the two 1-cyclohexyl-1-(4-fluorophenyl)-3-piperidyl-1-propanols and their methiodides.

Four new putative muscarinic antagonists, (R)-(-)- and (S)-(+)-1-cyclohexyl-1-(4-fluorophenyl)-3-piperidyl-1-propanol and their methiodides, have been synthesised. Absolute configurations have been assigned on the basis of the anticipated chirality of the products of the Sharpless asymmetric epoxidation reaction.

Identification and quantification of trihexyphenidyl and its hydroxylated metabolite by gas chromatography with nitrogen-phosphorus detection.

A sensitive and specific assay for the simultaneous quantification of trihexyphenidyl and its hydroxylated metabolite in plasma and urine is described. The method is based on the extraction of the drugs with an organic solvent and separation on a 3% OV-17 Chromosorb Q column in a gas chromatograph equipped with a nitrogen-phosphorus detector. The procedure employs SKF 525 A as the internal standard and requires no derivatization. The detection limit was found to be 2 ng/mL for trihexyphenidyl and 1 ng/mL for its metabolite. The precision of the assay procedure for both compounds is about 4 to 7%.

Nausea and vomiting after anesthesia and minor surgery.

The antiemetic effects of droperidol, diphenidol, and placebo were compared in 210 patients subjected to minor gynecologic or urologic procedures. Atropine (0.6 mg), meperidine (1 mg/kg) body mass, and either droperidol (5 mg), diphenidol (40 mg), or 2 ml of 0.9% saline were administered IM, 1 hour before general anesthesia. Trial drugs were presented in coded ampules so that the study was conducted double-blind. Droperidol appeared superior to both diphenidol (p less than 0.01) and placebo (p less than 0.001) in the prevention of vomiting, and reduced the incidence of nausea when compared to saline (p less than 0.05). Forty-four patients experienced side effects, which occurred with similar frequency in the 3 groups studied.