Disease relevance of RU 24969

• In rats the hypothermia induced by 8-OH-DPAT was partially antagonised by TVX Q 7821 while the behavioural "serotonin syndrome" induced by 8-OH-DPAT (a possible post-synaptic 5-HT1B-mediated effect) was unaffected by TVX Q 7821 as was the locomotion induced by RU 24969 [1].
• RU 24969-induced emesis in the cat: 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1C implicated [2].
• Unlike in the rat, RU 24969 did not elicit hypotension in the pig [3].
• The 5-HT2A/2C receptor agonist DOI (10-20 nmol/0.5 microliter) significantly reduced NPY overeating while the 5-HT1A/1B receptor agonist RU 24969 (3.5-14 nmol/0.5 microliter) and the 5-HT1B/2C receptor agonist mCPP (5-20 nmol/0.5 microliter) had no such effect [4].
• The mixed 5-HT-1A and 5-HT-1B agonist RU 24969 reversed catalepsy only at the highest dose tested [5].

Psychiatry related information on RU 24969

• Locomotor activity produced in mice by RU 24969 (3 mg kg-1) was antagonized by (-)-propranolol (20 mg kg-1) but not the (+)-isomer [6].
• Repeated administration of electroconvulsive shock, however, did produce an enhanced locomotor response to RU 24969 [7].
• Both 8-OH-DPAT (0.5-2.0 mg/kg, s.c.) and RU 24969 (0.5-2.0 mg/kg, s.c.) increased wakefulness and the latencies of slow wave and rapid eye movement (REM) sleep [8].

High impact information on RU 24969

• Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone [9].
• In the absence of VIP, cAMP formation could be stimulated through a 5-HT receptor, but the specific 5-HT1A agonists, 8-OH-DPAT and RU 24969 did not stimulate cAMP production [10].
• RU 24969 significantly reduced Bmax 23 to 63% in cortex, hippocampus, striatum, brainstem, and spinal cord without a change in Ka except for a 1.7-fold increase in cortex and spinal cord [11].
• Using the Behavioral Pattern Monitor (BPM), the profile of behavioral effects of a 5-HT1B agonist, 5-methoxy-3(1,2,3,6)tetrahydropyridin-4yl)-1H-indole (RU 24969), was compared to that previously described for MDMA and related indirect 5-HT agonists [12].
• The ability of RU 24969 (0.5, 1, 5, and 10 mg/kg, ip) to elevate PRL secretion was not inhibited by pretreatment with p-chlorophenylalanine, suggesting that RU 24969 stimulates PRL secretion only through activation of postsynaptic 5-HT receptors [13].

Chemical compound and disease context of RU 24969

• In a second series of experiments, administration of GR 127935 10 min after the onset of activity recordings promoted a dose-dependent decrease in basal activity (and rearings) and prevented (3.3 and 10 mg/kg) RU 24969-elicited locomotor activity [14].
• Locomotor activity induced by RU 24969 was markedly antagonised by haloperidol despite its lack of effect on the anorexic response [15].

Biological context of RU 24969

• Some behavioural and biochemical consequences of the administration of RU 24969 (5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole), a drug which has been shown to be a potent displacing agent at the 5-HT1 binding site, have been studied in mice and rats [7].
• The results support the view that RU-24969 stimulates a 5-HT1 receptor that is involved in the autoregulation of 5-HT release and metabolism [16].
• When animals were restrained from moving, RU 24969 dose-dependently reduced body temperature, an effect that may also be associated with activation of the 5-HT1A recognition site [17].
• In contrast to these results medial hypothalamic infusion of TFMPP or RU 24969 (12.5-50 nmol) failed to affect food intake in any of the 3 tests [18].
• Additionally, this study quantitatively examined the effect of quinpirole pretreatment on the ability of RU-24969 to induce both locomotor hyperactivity and striatal immediate early gene expression [19].

Anatomical context of RU 24969

• This residual 49% of [3H]5-HT binding to spinal cord synaptosomes observed in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969 (subsequently referred to as "5-HT1S") displayed high affinity and saturability (KD = 4.7 nM) in association/dissociation and saturation experiments [20].
• The 5-HT1A/1B receptor agonist RU 24969 was 10 times more potent at inhibiting [3H]5-HT overflow in the rat frontal cortex than in the human neocortex [21].
• The effect of RU 24969 infusion (1 microM) was attenuated by concurrent infusion of metitepine (10 microM) into the hippocampus [22].
• RU-24969 2.5 and 5 mg/kg had no effect on DA synthesis in the striatum, while 5.0 mg/kg significantly increased it in the nucleus accumbens [23].
• In some brain areas such as the globus pallidus and dorsal subiculum, binding of ICYP was blocked with high affinity by some serotoninergic ligands, RU-24969 and serotonin, but not by lysergic acid diethylamide and 8-hydroxy-2-(N,N-di-n-propylamino)tetralin [24].

Associations of RU 24969 with other chemical compounds

• Although the effects of MDMA on 5-HT1B receptors are secondary to its ability to release presynaptic 5-HT, the activation produced by RU 24969 appears to be a consequence of its direct agonist effects [12].
• Ipsapirone (0.25-5.0 mg/kg) increased OTR and at 1.0 mg/kg antagonised the anxiogenic action of 8-OH-D-PAT, RU 24969 and BAY R 1531 [25].
• The non-selective 5-HT antagonist metergoline prevented the RU-24969-induced decrease in 5-HT release and metabolism in vivo while the 5-HT2 receptor antagonist R-55669 (ritanserin) did not [16].
• 3. The affinities of 8-OH-DPAT, RU 24969 and methysergide determined against [3H]-idazoxan binding to the cortex and hippocampus correlate significantly with the binding site displaying low affinity for prazosin and previously designated alpha 2A [26].
• The relative potency, 8-hydroxy-2-(di-n-propylamino)tetra lin (8-OH-DPAT) much greater than 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) greater than or equal to 5-methoxy-3(tetrahydropyridin-4-yl)1H-indole (RU 24969), was unrelated to the occurrence of wet dog shakes and suggests that 5-HT1 rather than 5-HT2 receptors may be involved [27].

Gene context of RU 24969

• RU 24969, a tetrahydropyridoindole derivative that is a potent 5-HT1A and 5-HT1B agonist was also inactive, whereas RU 28253, another member of this series, could stimulate cAMP production [28].
• The 5-HT1A/1b agonist, RU 24969 (0.03-0.3 mg/kg), reduced chain lengths [29].
• Inasmuch as 5-HT2 receptors mediate the serotonergic stimulation of renin secretion, we examined the ability of two selective 5-HT2 antagonists, ritanserin and LY53857, to inhibit the neuroendocrine effects of RU 24969 [30].
• Because the 5-HT1B agonist RU 24969 disrupts PPI and stimulates locomotor behavior in rats, it was predicted that the 5-HT1D agonist, SDZ 219-964, would demonstrate a similar behavioral profile in guinea pigs [31].
• The cardiovascular effects of RU 24969 were antagonized neither by MDL 72222 nor by ICS 205-930 (5-HT3 receptor antagonists) [32].

Analytical, diagnostic and therapeutic context of RU 24969

• The pharmacological responses to intraperitoneal injection of the serotonin (5-HT) 5-HT1 agonist RU 24969 (0.25-5 mg/kg) were studied in rats either after single administrations or after repeated treatment (5 mg/kg per day for 3 days) [33].
• Using the radioactive microsphere technique in anaesthetized pigs, we studied the systemic and carotid haemodynamic effects of intracarotid infusions (0.3, 1, 3 and 10 micrograms/kg.min) of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969), a drug with high affinity for 5-HT1A and 5-HT1B recognition sites [3].
• 2. Exposure to increasing concentrations of 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate (RU 24969) (0.001-0.1 microM) during continuous electrical stimulation produced a concentration-dependent decrease in tritium overflow [34].
• We have compared the ability of the new putatively specific 5-HT1B receptor agonist CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b] pyrid-5-one) and the structurally related mixed 5-HT1A/5-HT1B receptor ligand RU 24969, to influence 5-HT release in brain in vivo, using microdialysis techniques in chloral hydrate-anaesthetised rats [35].
• GR 127935 blocks the locomotor and antidepressant-like effects of RU 24969 and the action of antidepressants in the mouse tail suspension test [36].

References