Inhibition of animal models of autoimmune disease and the induction of non-specific suppressor cells by SK&F 105685 and related azaspiranes.
SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride), administered orally to adjuvant arthritic (AA) rats inhibited immune-mediated hindpaw inflammation with an ED50 of 20 mg/kg/day. Both prophylactic and therapeutic administration were effective in this model. In addition, SK&F 105685 inhibited skin wheal responses to purified protein derivative (PPD) of tuberculin in AA rats and the development of hindleg paralysis associated with experimental allergic encephalomyelitis (EAE). Spleens of normal rats treated with SK&F 105685 were found to contain a population(s) of suppressor cells (SC) which inhibited the response of normal cells to Concanavalin A (Con A) in co-culture assays. The association between SC induction and anti-arthritic activity was determined by evaluating a series of chemically related azaspiranes in the AA rat model and for SC induction in normal rats. A statistically significant correlation was demonstrated (r = 0.79, P less than 0.001), indicating that SC induction may be responsible for the therapeutic activity of these compounds.
Badger
A M
AM
Department of Immunology, Smith Kline and French Laboratories, King of Prussia, PA 19406-0939.
Dimartino
M J
MJ
Talmadge
J E
JE
Picker
D H
DH
Schwartz
D A
DA
Dorman
J W
JW
Mirabelli
C K
CK
Hanna
N
N
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D008221:Lymphoid Tissue / Q000528:radiation effects; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D000276:Adjuvants, Immunologic; D013141:Spiro Compounds; C062162:SK&F 105685