Calcium regulating activity of 24a-homo-24,24-difluoro-1 alpha,25-dihydroxyvitamin D3 and 26,27-dimethyl-24,24-difluoro-1 alpha,25-dihydroxyvitamin D3.
Two fluoro analogs of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], 24a-homo-24,24-difluoro-1 alpha,25-dihydroxyvitamin D3 [24aF2-homo-1,25(OH)2D3], and 26,27-dimethyl-24,24-difluoro-1 alpha,25-dihydroxyvitamin D3 [24F2-1,25(OH)2(Me)2D3] were examined for calcium (Ca)-regulating activity. The objective of the present study was to determine whether or not fluoro substitution at 24-position would alter activities of the original compounds, that is, 26,27-dimethyl 1 alpha,25-dihydroxyvitamin. D3[1,25(OH)2(Me)2D3] and 24-homo-1 alpha,25-dihydroxyvitamin D3 [24homo-1,25(OH)2D3], respectively. The relative activities of 24aF2-homo-1,25(OH)2D3, 24F2-1,25(OH)2(Me)2D3, and 1,25(OH)2D3 in competing with 1,25(OH)2D3 for binding to chick intestinal cytosol receptor were 0.28:0.5:1.0. The relative potencies of the same series of compounds in competition for the vitamin D-deficient rat serum binding sites were 0.04:0.15:1. Bone-resorbing activities of two fluoro analogs in cultures of neonatal mouse parietal bones were more potent than that of 1,25(OH)2D3. Similar results were recognized in stimulating activities of osteoclast-like cell formation. Responses of two fluoro analogs to intestinal Ca absorption were similar to that of 1,25(OH)2D3. The potencies of 1,25(OH)2D3 and its fluoro analogs in bone Ca mobilization were the highest with 1,25(OH)2D3, followed by 24F2-1,25(OH)2(Me)2D3 and 24aF2-homo-1,25(OH)2D3, in that order. From these results and the data of Paulson et al., fluoro substitution in 24-position of 1,25(OH)2D3 apparently does not alter their activities,hence, the fluoro substitution at 24-position of 1,25(OH)2D3 and the elongation of side chain of 1,25(OH)2D3 may not intensify Ca-regulating activity.
Harada
M
M
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Miyahara
T
T
Miyata
M
M
Komiyama
H
H
Sugure
A
A
Ikemoto
Y
Y
Kondo
S
S
Takamura
T
T
Higuchi
S
S
Otomo
S
S
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001851:Bone Diseases, Metabolic / Q000517:prevention & control; D001862:Bone Resorption / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002645:Chickens; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010010:Osteoclasts / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; C085358:26,27-dimethyl-24,24-difluoro-1,25-dihydroxyvitamin D3; C055039:24,24-difluoro-24-homo-1,25-dihydroxyvitamin D3; D002117:Calcitriol; D002118:Calcium