Isamoltane hemifumarate

Prophylactic effects of asiaticoside-based standardized extract of Centella asiatica (L.) Urban leaves on experimental migraine: Involvement of 5HT1A/1B receptors.[Pubmed:25908624]

Chin J Nat Med. 2015 Apr;13(4):274-82.

The present study aimed at evaluation of prophylactic efficacy and possible mechanisms of asiaticoside (AS) based standardized extract of Centella asiatica (L.) Urban leaves (INDCA) in animal models of migraine. The effects of oral and intranasal (i.n.) pretreatment of INDCA (acute and 7-days subacute) were evaluated against nitroglycerine (NTG, 10 mg.kg(-1), i.p.) and bradykinin (BK, 10 mug, intra-arterial) induced hyperalgesia in rats. Tail flick latencies (from 0 to 240 min) post-NTG treatment and the number of vocalizations post-BK treatment were recorded as a measure of hyperalgesia. Separate groups of rats for negative (Normal) and positive (sumatriptan, 42 mg.kg(-1), s.c.) controls were included. The interaction of INDCA with selective 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonists (NAN-190, Isamoltane hemifumarate, and BRL-15572 respectively) against NTG-induced hyperalgesia was also evaluated. Acute and sub-acute pre-treatment of INDCA [10 and 30 mg.kg(-1) (oral) and 100 mug/rat (i.n.) showed significant anti-nociception activity, and reversal of the NTG-induced hyperalgesia and brain 5-HT concentration decline. Oral pre-treatment with INDCA (30 mg.kg(-1), 7 d) showed significant reduction in the number of vocalization. The anti-nociceptive effects of INDCA were blocked by 5-HT1A and 5-HT1B but not 5-HT1D receptor antagonists. In conclusion, INDCA demonstrated promising anti-nociceptive effects in animal models of migraine, probably through 5-HT1A/1B medicated action.

Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1 receptor subtypes in the rat brain.[Pubmed:2905765]

Naunyn Schmiedebergs Arch Pharmacol. 1988 Jun;337(6):609-20.

Isamoltane (CGP 361A; (1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol hydrochloride), a beta-adrenoceptor ligand (IC50 = 8.4 nmol/l) which has reported activity as an anxiolytic in man was found to be a reasonably active inhibitor of the binding of [125I]ICYP to 5-HT1B recognition sites in rat brain membranes with 27-fold selectivity (IC50 = 39 nmol/l) as compared to the inhibition of binding of [3H]8-OH-DPAT to 5-HT1A receptors (IC50 = 1070 nmol/l). This selectivity was considerably greater than that observed for other beta-adrenoceptor ligands including propranolol (5-HT1A/5-HT1B ratio = 2), oxpenolol (3.5) and cyanopindolol (8.7). The 5-HT1B activity of the compound resided in the (-)-enantiomer. (-)-Isamoltane had weak activity (IC50 3-10 mumol/l) at 5-HT2 and alpha 1-adrenoceptors. The compound was devoid of activity at a number of other central neurotransmitter recognition sites including the 5-HT1C site. Isamoltane increased the electrically evoked release of [3H]5-HT from prelabeled rat cortical slices in a manner similar to that of cyanopindolol. While both compounds were similar in potency to methiothepin, they had lower efficacy. Oxprenolol was less potent that both isamoltane and cyanopindolol while propranolol was essentially inactive. The effects of the compounds on 5-HT release appeared to be correlated with their 5-HT1B rather than 5-HT1A activity. In vivo, isamoltane increased 5-HTP accumulation in rat cortex following central decarboxylase inhibition at doses of 1 and 3 mg/kg i.p. At higher doses this effect was gradually diminished. Similar, but less clearcut results were obtained with cyanopindolol and oxprenolol, but propranolol was ineffective. No changes in brain tryptophan levels were associated with the isamoltane-evoked changes in brain 5-HTP levels. In reserpinized animals, isamoltane reduced 5-HTP accumulation even at doses which enhanced accumulation of this metabolite when given alone. The effects of the putative 5-HT1B agonist, m-trifluoromethylphenylpiperazine (TFMPP), the mixed 5-HT autoreceptor agonist/antagonist/beta-adrenoceptor antagonist, pindolol, the 5-HT uptake inhibitor, CGP 6085A and the MAO-A inhibitor, brofaromine, were not antagonized by pretreatment with isamoltane. The possibility that isamoltane and the other beta-adrenoceptor antagonists are antagonists at 5-HT1B receptors and that their effect on 5-HT synthesis in vivo is the net result of their agonist/antagonist effects at 5-HT1A and 5-HT1B receptors is discussed in relation to the potential mechanism of the anxiolytic activity of isamoltane.