Concerning the pharmacological activity of non-steroid anti-inflammatory drugs: Is the acidic function essential?

Abstract

There are scattered reports, mainly in the patent literature, indicating that certain primary alcohols, amines and other nonacidic derivatives of nonsteroidal anti-inflammatory (NSAI) acidic drugs display anti-inflammatory activity (see for example [1,2]). This is of more than academic interest for, besides expanding the structure-:'action relationships, these reports may indicate a possible means of improving the therapeutic: ulcerogenic index of effective NSAI agetats.The assumption that these particular nonacidic agents must owe their in vivo activity to bioeffective acidic metabolites, has not been rigorously questioned. This communication presents evidence that a variety of NSAI car~boxylic acids and their corresponding primary alcohols have very similar effects on cellular metabolism. In fact, these particular alcohols are rather more potent than the acids under in vitro conditions which preclude their rapid conversion to the related acids. :ExperimentalDrugs and carbinols were added to incubations of lymphocytes and various radioactive ions or metabolites, from solutions in DMSO or DMF yielding a final concentration of organic solvent never exceeding 2 % v/v DMF or 1% v/v DMSO. The incorporation of thymidine-6-3H 1) Present Address:

About some biochemical properties of dimethylsulfoxide and three of its homologues: Is the acidic function essential for nonsteroidal antiinflammatory activities?

“…but are also demonstrated by related alcohols (and even hydrocarbones) often at much lower concentrations than the N.S.A.I. acids [25]. It appears that DMSO and three other sulfoxides may exhibit such biochemical properties which could certainly affect the (ab)normal functioning of the tissues to which they were applied in high concentration (as in a topical application).…”

“…logues (n-propyl sulfoxide, n-butyl sulfoxide and tetramethylene sulfoxide) affect any of the biochemical parameters known to be influenced by nonsteroidal antiinflammatory drugs (N.S.A.I.D.). These include the uncoupling of mitochondrial oxidative phosphorylation [20], mitochondrial [21] and lymphocyte [22] swelling, inhibition of aH-nucleoside incorporation into nucleic acids and 14C-amino-acids into proteins of lymphocytes [23] and changes induced in cell membrane permeability as expressed by effects on 86Rb, la4Cs, Z2Na and 45Ca uptake by lymphocytes [24,25,26].…”