MDL 72832 hydrochloride

MDL 72832 hydrochloride is a potent and selective ligand for 5-HT1A receptor with pIC50 value of 9.1 [1].

The 5-HT1A receptor is a G protein-coupled receptor for endogenous neurotransmitter serotonin (5-HT) and mediates inhibitory neurotransmission.

MDL 72832 hydrochloride is a potent and selective ligand for 5-HT1A receptor [1]. Also, MDL 72832 exhibited affinity with pKD values of 6.32 and 6.34 for 5-HT1C and 5-HT1D receptors, respectively [1].

In rats, MDL 72832 inhibited 8-OH-DPAT-induced cardiovascular effects. In guinea-pigs, 8-OH-DPAT inhibited the contraction of the field-stimulated guinea-pig ileum in a concentration-dependent way. While MDL 72832 inhibited 8-OH-DPAT-induced neuronal inhibition. MDL 72832 is a ligand for 5-HT1A receptor with mixed antagonist and agonist properties [1]. In pre-satiated rats, (+) -MDL 72832 (1.0 mg/kg) stimulated food intake and (-) -MDL 72832 (0.03 mg/kg) significantly increased food intake [2]. In rats, MDL 72832 increased postsynaptic 5-HT1A receptors mediating hypothermia and exhibited agonist property [3].

References:
[1].  Mir AK, Hibert M, Tricklebank MD, et al. MDL 72832: a potent and stereoselective ligand at central and peripheral 5-HT1A receptors. Eur J Pharmacol, 1988, 149(1-2): 107-120.
[2].  Neill JC, Cooper SJ. MDL 72832, a selective 5-HT1A receptor ligand, stereospecifically increases food intake. Eur J Pharmacol, 1988, 151(2): 329-332.
[3].  Millan MJ, Rivet JM, Canton H, et al. Induction of hypothermia as a model of 5-hydroxytryptamine1A receptor-mediated activity in the rat: a pharmacological characterization of the actions of novel agonists and antagonists. J Pharmacol Exp Ther, 1993, 264(3): 1364-1376.

Induction of hypothermia as a model of 5-hydroxytryptamine1A receptor-mediated activity in the rat: a pharmacological characterization of the actions of novel agonists and antagonists.[Pubmed:8450471]

J Pharmacol Exp Ther. 1993 Mar;264(3):1364-76.

In this study, we examined the localization of the 5-hydroxytryptamine (5-HT)1A receptors mediating hypothermia in the rat, evaluated the pharmacological specificity of this response and examined the influence of a series of novel 5-HT1A receptor ligands upon core temperature. Administered s.c., 8-hydroxy-(2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), an agonist at both pre- and postsynaptic 5-HT1A receptors, elicited pronounced hypothermia. In contrast, BMY 7378, which shows low efficacy at postsynaptic 5-HT1A receptors but high efficacy at presynaptic 5-HT1A receptors, elicited only mild hypothermia. Similarly, 8-OH-DPAT was more efficacious than BMY 7378 in eliciting corticosterone secretion, a response mediated by postsynaptic 5-HT1A receptors, whereas BMY 7378 was as efficacious as 8-OH-DPAT in inhibiting striatal accumulation of 5-hydroxytryptophan, a response mediated by presynaptic 5-HT1A receptors. These data suggest, by analogy, that postsynaptic 5-HT1A receptors mediate hypothermia, an interpretation supported by the observation that destruction of central 5-HT neurons with 5,7-dihydroxytryptamine failed to reduce 8-OH-DPAT-induced hypothermia (DIH). Agonists at 5-HT1B, 5-HT1C, 5-HT2 and/or 5-HT3 receptors did not elicit hypothermia, and drugs releasing 5-HT elicited hyperthermia. In contrast, DIH was fully mimicked by the novel 5-HT1A receptors agonists, eltoprazine, WY 48,723, MDL 72832, tandospirone, S 14671, S 14506 and WY 50,324, whereas the novel partial agonist, zalospirone, was less efficacious. DIH was blocked by (-)-alprenolol, (+/-)-pindolol and the novel beta-blocker, (-)-tertatolol, which also has high affinity for 5-HT1A receptors; in distinction, betaxolol and ICI 118,551, antagonists at beta-1 and beta-2 adrenoceptors, respectively, were inactive. Spiperone, NAN-190 and BMY 7378 also inhibited DIH whereas ritanserin, SCH 39166, raclopride and prazosin, antagonists at 5-HT2 receptors, D1 and D2 dopamine receptors and alpha-1 adrenoceptors, respectively, were inactive. The novel 5-HT1A antagonists, WAY 100,135, MDL 73005 EF and (very potently) SDZ 216-525 all blocked DIH. Potency for induction of hypothermia and inhibition of DIH correlated well with affinity for 5-HT1A binding sites. In conclusion, hypothermia is a highly specific and sensitive response to activation of postsynaptic 5-HT1A receptors. Furthermore, DIH is inhibited by their selective blockade. At postsynaptic 5-HT1A receptors mediating hypothermia, eltoprazine, WY 48,723, MDL 72832 and tandospirone are agonists, zalospirone is a partial agonist and (-)-tertatolol, WAY 100,135, MDL 73005 EF and SDZ 216-525 are antagonists.

MDL 72832: a potent and stereoselective ligand at central and peripheral 5-HT1A receptors.[Pubmed:2840295]

Eur J Pharmacol. 1988 Apr 27;149(1-2):107-20.

In receptor binding assays (+/-)MDL 72832, 8-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]-8-azaspiro++ +[4,5] decane-7,9-dione, was a potent (pIC50 9.1), selective and stereospecific ligand for central 5-HT1A recognition sites. In functional tests, (+/-)MDL 72832 and its S(-) and R(+) enantiomers blocked stereoselectively the 8-OH-DPAT-induced neuronal inhibition of the transmurally stimulated guinea-pig ileum and the cardiovascular effects of 8-OH-DPAT in anaesthetized rats. In contrast, (+/-)MDL 72832 and its enantiomers were exclusively '8-OH-DPAT-like' in their ability to fully and stereoselectively generalize to the 8-OH-DPAT discriminative stimulus and, in reserpinised rats, to induce forepaw treading and flat body posture. These results characterize (+/-)MDL 72832 as a potent, stereoselective ligand with mixed agonist and antagonist properties at central and peripheral 5-HT1A receptors. The similar stereoselective requirements for the recognition site and functional effects provides compelling evidence that the 5-HT1A recognition site is indeed a functional receptor.