(Aminoalkyl)carbamates of forskolin: intermediates for the synthesis of functionalized derivatives of forskolin with different specificities for adenylyl cyclase and the glucose transporter.
(Aminoalkyl)carbamates of forskolin were synthesized at the 6- and 7-hydroxyl positions of forskolin with the length of the alkyl chain varying from ethyl to heptyl. Two of these derivatives, 7-[[(2-aminoethyl)amino]carbonyl]-7-desacetylforskolin (2) and 6-[[(2-aminoethyl)amino]carbonyl]forskolin (3), were used to synthesize iodinated derivatives of forskolin that bind with high affinity to adenylyl cyclase in bovine brain membranes and the glucose transporter in human erythrocyte membranes, respectively. Hydroxyphenyl derivatives of forskolin were prepared from the (aminoalkyl)carbamates and tested for their ability to bind to adenylyl cyclase in bovine brain membranes and the glucose transporter in human erythrocyte membranes. The 6-derivative (18) of forskolin had a Kd of 9 nM at adenylyl cyclase and was more potent than either the 7-derivatives or the 6-derivatives of 7-desacetylforskolin. The 7-derivatives were more potent at binding to the glucose transporter than forskolin. In contrast, the 6-derivatives had Kd's greater than 100 microM at the glucose transporter. Isothiocyanates and N-bromoacetyl derivatives were synthesized from 2 and 3 as potential alkylating agents for forskolin binding sites. The alkylating agents produced an irreversible loss of forskolin binding to adenylyl cyclase. In contrast, the alkylating agents bound reversibly to the glucose transporter.
Robbins
J D
JD
Laboratory of Molecular Pharmacology, Food and Drug Administration, Bethesda, Maryland 20892.
Laurenza
A
A
Kosley
R W
RW
O'Malley
G J
GJ
Spahl
B
B
Seamon
K B
KB
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002219:Carbamates; D009004:Monosaccharide Transport Proteins; D005576:Colforsin; D000262:Adenylyl Cyclases; D005947:Glucose