(+)- and (-)-3-Methoxycyproheptadine. A comparative evaluation of the antiserotonin, antihistaminic, anticholinergic, and orexigenic properties with cyproheptadine

Abstract

The synthesis and resolution of (+/-)-3-methoxycyproheptadine [(+/-)-4] are described. As a peripheral serotonin antagonist, (+/-)-4 was found to be one-half as potent as cyproheptadine (1b). The peripheral anticholinergic and antihistaminic activities as well as the orexigenic property of (+/-)-4 are less than those of 1b. A further comparison of the enantiomers (+)-4 and (-)-4 shows that all of the anticholinergic activity of (+/-)-4 resides solely in the dextrorotatory enantiomer, (+)-4, while the antiserotonin activity, which is similar to that of 1b, resides in the levorotatory enantiomer, (-)-4. Antihistaminic and orexigenic activity also resides in (-)-4 but these properties are reduced compared to those of 1b.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…7), some conformational isomers have been observed. Normally these compounds undergo a rapid intraconversion, but in some cases the orientation of the piperidine moiety on the bend ring system remains stable and the remaining atropisomers (conformational enantiomers) can be separated (Remy et al, 1977;Randall et al, 1979). It is unclear if these effects can also be observed in vivo.…”

Optical Isomerism in Drugs

“…Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (1)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (2)-HA-966 is a potent γ-butyrolactone-like sedative [50]. A comparison of (1) and (2)-3methoxycyproheptadine shows that all of the anticholinergic activity of the ( 6 )-3-methoxycyproheptadine resides solely in the dextrorotatory enantiomer, while the antiserotonin activity resides in the levorotatory enantiomer [51]. Table 18.5 shows some experimental data for the active isomers of the fluoro analogs of the tricyclic neuroleptic clotepin as compared to the corresponding racemate [53].…”

Optically active analogues of ebastine: Synthesis and effect of chirality on their antihistaminic and antimuscarinic activity

“…To determine the conformational preferences of the piperidine ring system of 6, a nortropine analogue benztropine (1 1, Scheme 4) (antihistamine PA, 9.4 and antimuscarinic PA, 9. 77) was incorporated in the modelling study.…”