SKF 91488 dihydrochloride

Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301 U, in rodent antinociception.[Pubmed:9089666]

Naunyn Schmiedebergs Arch Pharmacol. 1997 Mar;355(3):354-60.

We have previously reported that the histaminergic system is involved in the control of pain perception, and that substances able to enhance histamine brain levels, such as the histamine-N-methyltransferase inhibitor, metoprine, induce antinociception. In the present study, in order to corroborate the idea of inducing antinociception by inhibiting histamine catabolism, the effects of a noncompetitive histamine-N-methyltransferase inhibitor. SKF 91488, were studied in rodents by means of tests inducing three different kinds of noxious stimuli: thermal (mouse hot plate), chemical (mouse abdominal constrictions) and mechanical (rat paw pressure). The ability to react to noxious stimuli was assessed by the rota-rod test. In addition, a competitive inhibitor of the histamine catabolism enzyme, BW 301 U, was studied in the hot plate test. SKF 91488 (30, 50 and 100 micrograms per animal i.c.v.) raised dose-dependently the pain threshold in all three tests. To verify whether SKF 91488-induced antinociception is due to inhibition of histamine-N-methyltransferase, (R)-alpha-methylhistamine, described to block histamine release and synthesis by stimulating the histamine H3-autoreceptor and activating the negative feed-back mechanism, was used. When administered at doses which do not alter the pain threshold per se, 0.5 microgram per rat i.c.v. or 10 mg kg-1 i.p. in mice, (R)-alpha-methylhistamine was able to antagonize significantly the antinociceptive effect induced by 30 micrograms per animal i.c.v. of SKF 91488. BW 301 U (30 and 100 mg kg-1 i.p.) showed a dose-dependent, long-lasting antinociception, which was also antagonized by pretreatment with (R)-alpha-methylhistamine. The present data show that the antinociceptive effect previously described for metoprine is not restricted to this molecule, but is also shared by other histamine-N-methyl-transferase inhibitors. This generalization provides further evidence to the importance of the histaminergic system in pain control mechanisms.

Histamine N-methyltransferase controls the contractile response of guinea pig trachea to histamine.[Pubmed:1534842]

J Pharmacol Exp Ther. 1992 Jun;261(3):1268-72.

The contractile response of isolated guinea pig trachea to histamine was potentiated in the presence of the histamine N-methyltransferase (HMT) inhibitor SKF 91488, whereas the diamine oxidase inhibitor aminoguanidine was without effect. SKF 91488 shifted in a concentration-dependent fashion the concentration-response curves to histamine to lower concentrations with the maximum by 1 log unit. The trachea contained significant HMT activity (45.4 +/- 5.0 pmol/min/mg protein). In situ hybridization to detect HMT mRNA indicated that HMT mRNA was present in the epithelium and endothelium, being more abundant in the former. Removal of the epithelium shifted the concentration-response curves to histamine to lower concentrations by 0.8 log unit, and SKF 91488 caused only a slight shift of histamine concentration-response curves in tissues denuded of epithelium. These findings suggest that HMT regulates the contractile response of guinea pig trachea to histamine, and epithelial removal-induced bronchial hyperresponsiveness to histamine is largely explained by the loss of HMT in the epithelium.

Inhibition of histamine methylation in vivo by the dimaprit analog, SKF Compound 91488.[Pubmed:161853]

Agents Actions. 1979 Dec;9(5-6):455-60.

The Dimaprit analog, S-[4-(N,N-dimethylamino)-butyl]isothiurea (SKF Compound 91488), which is a noncompetitive inhibitor (Ki, 0.9 microM) of histamine-N-methyltransferase in vitro, inhibited the methylation of labeled histamine in mice. When administered in combination with the diamine oxidase inhibitor, aminoguanidine, an almost complete block of histamine metabolism was observed. The inhibition was dependent on dose of drug and was apparent with doses of 50 mg/kg and greater. Since Compound 91488 is reported to have no agonist activity of its own, the drug may help to identify the actions of histamine released from endogenous stores in response to physiological and pathological stimuli.