Studies in antifertility agents. 50. Stereoselective binding of d- and l-centchromans to estrogen receptors and their antifertility activity

Abstract

Centchroman [dl-3,4-trans-2,2-dimethyl-3-phenyl-4-[p-(beta-pyrrolidinoethoxy)phenyl] - 7-methoxychroman hydrochloride], an antifertility agent under clinical evaluation, has been resolved into its optical enantiomers. The cytosol estrogen receptor binding affinity and estrogenic, antiestrogenic and antiimplantation activities of the two enantiomers have been determined. The enantiomers display a 7-fold difference in receptor affinity, and a corresponding difference in stimulation of the uterine growth and antiimplantation activity was observed in rats.

Differential Effects of Estrogen and Raloxifene on Messenger RNA and Matrix Metalloproteinase 2 Activity in the Rat Uterus

“…Subsequent studies used Sprague Dawley rats of various age ( Table 1) that were housed and fed as described above. Levormeloxifene and lasofoxifene were synthesized as described previously [20,21] and were dosed orally in study 6 in addition to Ral at 3, 0.3, and 0.03 mg kg Ϫ1 day Ϫ1 . Animals were fasted the night before termination of each study, and all animal procedures were reviewed before implementation by an internal animal welfare committee to ensure compliance with National Institutes of Health guidelines.…”

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone‐related clinical disorders

“…30 Transposition of pyrrolidinoethoxy chain to ortho-(RBA: 0.78 AE 0.14; 11) or meta-(RBA: undetectable; 12) positions on 4-phenyl ring or to para-position on 3-phenyl ring (RBA: 0.14 AE 0.03; 13) causes a marked decrease or total loss of receptor af®nity. 28 Introduction of 3-nbutylamino-2-hydroxypropyloxy moiety (14) in place of tert-b-aminoethoxy group, characteristic of SERMs possessing contraceptive property, led to 2.5±5-fold enhancement of anti-implantation activity of centchroman, 3,4-diaryl coumarins, and chromenes, and a signi®cant increase in RBA in accordance with estrogen agonistic activity. 22,131 In comparison, piperidine moiety in aminoalkoxy side chain 126 appears to reduce RBA of 3,4-cis-(undetectable; 16) and trans-(3.77 AE 0.25; 15) chromans with slight improvement in anti-implantation activity.…”

“…22,24±27 It has been resolved into D-and L-enantiomers by fractional crystallization of its D-and L-di-ptoluoyltartarate salts to constant rotation, liberation of free bases by alkaline hydrolysis and conversion to hydrochlorides. 28,29 The L-isomer is a more potent receptor binder with relative binding af®nity (RBA, to rat uterine cytosol estrogen receptors; percent of estradiol-17b) of 15.7 AE 3.1 30 and exhibits 33-and about two-fold higher anti-implantation activity in rat 28,31,32 than D-(RBA: 2.10 AE 0.9) or DL-centchroman (RBA: 5.24 AE 1.45), as its 3R, 4R absolute con®guration with axial methyl group at C-2 diverted downwards along C-7a axis of estradiol is well tolerated by estrogen receptor (ER) and makes the best ®t. 33 7-Desmethyl centchroman (Fig.…”

Effect of side-chain alteration on hormonal activity of nonsteroidal estrogen antagonists

“…The biological activity of different isomeric forms of centchroman has been reported earlier (Salman et al, 1986).…”

“…In the trans-diaryl chroman the l-enantiomer (3R,4R) of centchroman showed sevenfold higher relative binding affinity (RBA) as compared with the d-form, and similar order of difference in their estrogenic and antiestrogenic activities (Salman et al, 1986). However, its 100-fold lower RBA and low antiestrogenicity would suggest inferior binding of the hydrazide chain as compared with pyrrolidinoethoxy on the antiestrogen binding site of the receptor.…”