The novel 5-HT1A receptor antagonist (S)-UH-301 antagonizes 8-OH-DPAT-induced effects on male as well as female rat copulatory behaviour.

The 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) facilitates male rat copulatory behaviour but inhibits female rat copulatory behaviour. The effect of the novel 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [S)-UH-301) on these 8-OH-DPAT-induced responses was tested. 8-OH-DPAT was given s.c. in a dose of 0.176 mumol/kg (50 micrograms/kg). The doses of (S)-UH-301 given s.c. were 1.76 mumol/kg (0.53 mg/kg) and 5.28 mumol/kg (1.60 mg/kg). The administration of (S)-UH-301 10 min before 8-OH-DPAT antagonized the 8-OH-DPAT-induced effects on both male and female rat copulatory behaviour. The results presented strongly support the classification of (S)-UH-301 as a 5-HT1A receptor antagonist. In addition, the effect of the enantiomer of (S)-UH-301, (R)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [R)-UH-301), on male rat copulatory behaviour was tested. This enantiomer was found to facilitate male rat copulatory behaviour in a 8-OH-DPAT-like manner, supporting a 5-HT1A agonistic action of (R)-UH-301.     

The novel 5-HT1A receptor antagonist (S)-UH-301 prevents (R)-8-OH-DPAT-induced decrease in interstitial concentrations of serotonin in the rat hippocampus.

Previous studies have demonstrated that the novel 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) analogue (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin ((S)-UH-301) is able to antagonize several behavioural and biochemical effects of the 5-HT1A receptor agonist 8-OH-DPAT in the rat. In the present study in vivo microdialysis was used to evaluate the effects of (S)-UH-301 on interstitial concentrations of 5-hydroxytryptamine (5-HT), its metabolite 5-hydroxyindoloacetic acid (5-HIAA), and the catecholamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal hippocampus of freely moving rats. Furthermore, the effects of (S)-UH-301 on (R)-8-OH-DPAT-induced changes in dialysate hippocampal concentrations of 5-HT and metabolites were examined. Neither 5-HT nor metabolites were significantly influenced by (S)-UH-301 (1.25, 2.5, 5.0 mg/kg s.c.). In contrast, (R)-8-OH-DPAT (100 micrograms/kg s.c.) decreased interstitial concentrations of 5-HT (to 45% of baseline) and 5-HIAA (to 75%), and increased concentrations of DOPAC (to 165%) and HVA (to 155%). Pretreatment with (S)-UH-301 (2.5 mg/kg s.c.) 20 min before (R)-8-OH-DPAT (100 micrograms/kg s.c.) abolished the 5-HT and metabolite response to (R)-8-OH-DPAT. These data indicate that (S)-UH-301 is able to antagonize (R)-8-OH-DPAT-induced biochemical effects in vivo without producing any effects when given alone. Thus, the present study contributes to the characterization of (S)-UH-301 as a 5-HT1A receptor antagonist with low intrinsic activity.     

(R)- and (S)-8-acetyl-2-(dipropylamino)tetralin (LY-41): two novel 5-HT1A receptor agonists

Interactions between central 5-HT_1A receptors and the enantiomers of LY-41, a 2-aminotetralin derivative related to 8-OH-DPAT (8-hydroxy-2-(dipropylamino)tetralin), were studied. Both enantiomers of LY-41 behaved as potent 5-HT_1A receptor agonists in rats, inducing the 5-HT behavioural syndrome, decreasing body temperature and inhibiting the cage-leaving response. The behavioural syndrome and the hypothermia were antagonized by the 5-HT_1A receptor antagonist, (S)-UH-301. The LY-41 enantiomers also reduced brain 5-HTP accumulation in rats treated with a decarboxylase inhibitor. The pharmacology of the enantiomers of LY-41 appeared similar to that of 8-OH-DPAT. However, it is noteworthy that the stereoselective interaction of 5-HT_1A receptors with LY-41 was opposite to that of 8-OH-DPAT. Thus, (R)-8-OH-DPAT was more potent than (S)-8-OH-DPAT, whereas (S)-LY-41 appeared to be more potent than (R)-LY-41.     

(R)- and (S)-5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten- 8-ylamine. Stereoselective interactions with 5-HT1A receptors in the brain

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.     

An integrative pharmacokinetic and pharmacodynamic study of the 5-HT1A receptor antagonist (S)-UH-301 in the rat.

(S)-UH-301 ((-)-(S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin hydrochloride) is a well known 5-HT(1A) receptor antagonist. The present study describes the pharmacokinetic properties of (S)-UH-301 after subcutaneous administration in rats, using a newly developed HPLC-UV bioanalytical method. The relationships between (S)-UH-301 concentrations and some pharmacodynamic effects were also studied. The AUC of (S)-UH-301 in brain, but not in plasma, increased in proportion to dose (1-100 mumol/kg). However, at doses above 32 mumol/kg, peak concentrations of the drug did not increase in proportion to dose, and there was a doubling of its apparent half-life. There was a good correspondence between the time courses for the antagonism of 8-OH-DPAT-induced motor behaviours and hypothermia and the tissue concentrations of (S)-UH-301. Doses of (S)-UH-301 above 10 mumol/kg decreased 5-HT and dopamine synthesis. Therefore, a selective 5-HT(1A) antagonistic dose range of (S)-UH-301 should be 0.1-10 mumol/kg s.c., corresponding to concentrations below approximately 10 nmol/g in brain and approximately 1 nmol/ml in plasma.     

Intrinsic activity of enantiomers of 8-hydroxy-2-(di-n-propylamino)tetralin and its analogs at 5-hydroxytryptamine1A receptors that are negatively coupled to adenylate cyclase

Although many different types of compounds have been tested for 5-hydroxytryptamine1A (5-HT1A) binding affinity, much remains to be learned about the structural requirements associated with 5-HT1A agonism, partial agonism, and antagonism. The present study uses the forskolin-stimulated adenylate cyclase (FSC) assay as a functional screen in rat hippocampal membranes to examine structure-activity relationships for a series of enantiomers of novel analogs of the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The findings illustrate that there can be large enantiomeric differences in intrinsic activity at the 5-HT1A receptor, independent of enantiomeric effects on binding affinity. Generally, for each enantiomeric pair exhibiting stereoselective 5-HT1A binding, the enantiomer with the higher affinity also displayed the greater amount of 5-HT1A intrinsic activity in the FSC assay. Interestingly, the enantiomers of 8-OH-DPAT itself displayed stereoselective differences in intrinsic activity but not 5-HT1A affinity. Several of the compounds, namely (S)-UH-301, (2R,3R)-CM-12, and (1S,2R)-LEA-146, may have potential as prototypes for selective 5-HT1A antagonists, and (S)-UH-301 itself may be useful as a selective 5-HT1A antagonist. The FSC data presented here are in good agreement with reported measures of in vivo 5-HT1A activity, which were in part the basis of a recently proposed model for the 5-HT1A pharmacophore [J. Med. Chem. 34: 497-510 (1991)].     

The effect of 5-HT1A receptor agonists on locomotor activity in the guinea-pig.

1. The present study examined the effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), flesinoxan, ipsapirone and buspirone, all agonists at the 5-HT1A receptor, on the locomotor activity of guinea-pigs. The effects of these drugs were contrasted with those of the non-selective 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine (5-MeO-DMT) and the dopamine D2 antagonist, raclopride. 2. 8-OH-DPAT, flesinoxan and 5-MeO-DMT markedly increased the locomotor activity of naive, unhabituated guinea-pigs in a dose-dependent manner. Buspirone also did so, although to a lesser extent and for a shorter time. The doses at which this effect was seen were higher than those normally employed in rats. Ipsapirone and raclopride had no significant effects on locomotor activity. 3. The locomotor activity increasing effect of 1.0 mg kg-1 8-OH-DPAT was blocked by the selective 5-HT1A antagonist (S)-UH-301 (3.0 and 10.0 mg kg-1), but not by (-)-alprenolol (15.0 mg kg-1). Ipsapirone (30.0 mg kg-1) and raclopride (3.0 mg kg-1) antagonized 8-OH-DPAT-induced locomotor activity but only to a small extent. The 5-HT reuptake inhibitor, zimelidine (10.0 mg kg-1) had no effect. 4. The effect of the 5-HT1A agonists in the guinea-pig contrasts with the effects of 8-OH-DPAT on the locomotor activity of unhabituated rats and mice tested in the same apparatus, but are similar to the effects of 8-OH-DPAT on habituated rats, which show a low baseline of activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons

Summary The effects of the selective 5-HT_1A receptor agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HT_1A antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] were studied with regard to the firing pattern of single mesencephalic dopamine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with respect to firing rate, burst firing and regularity of firing. In the ventral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2–32 g/kg i.v.) caused an increase in all three parameters. The effect on firing rate of DA neurons was more pronounced in the parabrachial pigmentosus nucleus than in the paranigral nucleus, the two major subdivisions of VTA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2–256 g/kg i.v.) had no effect on firing rate and regularity of firing and only slightly increased burst firing. High doses of (R)-8-OH-DPAT (512–1024 g/kg i.v.) decreased the activity of DA cells in both areas, an effect that was prevented by pretreatment with the selective DA D₂ receptor antagonist raclopride. (S)-UH-301 (100–800 g/kg i.v.) decreased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firing rate but failed to affect burst firing and regularity of firing. These effects of (S)-UH-301 were blocked by raclopride pretreatment. Local application by pneumatic ejection of 8-OH-DPAT excited the DA cells in both the VTA and the SN-ZC, whereas (S)-UH-301 inhibited these cells when given locally. These results show that 5-HT_1A receptor related compounds differentially affect the electrophysiological activity of central DA neurons. The DA receptor agonistic properties of these compound appear to contribute to the inhibitory effects of high doses of (R)-8-OH-DPAT and (S)-UH-301 on DA neuronal activity. Given the potential use of 5-HT_1A receptor selective compounds in the treatment of anxiety and depression their effects on central DA systems involved in mood regulation and reward related processes are of considerable importance.Correspondence to T. H. Svensson at the above address     

Different behavioural profiles of the R(+)- and S(-)-enantiomers of 8-hydroxy-2-(di-n-propylamino) tetralin in the murine elevated plus-maze

(=) 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) has been the most widely used pharmacological tool in research on 5-HT(1A) receptor function. In the present study, the behavioural effects of 8-OH-DPAT entantiomers were compared using an ethological version of the murine elevated plus-maze test. Subcutaneous pretreatment (-20min) with R(+)-8-OH-DPAT (0.03-1.0mg/kg) produced a pronounced; and dose-dependent behavioural suppression (decreased open/closed/total arm entries and increased nonexploratory behaviours). In contrast, over the same dose range, S(-)-8-OH-DPAT reduced several ethological indices of anxiety without altering the majority of conventional parameters or general activity levels, e.g. arm entries and per cent time measures, as well as head dipping. Findings are discussed in relation to differences in the intrinsic activity of 8-OH-DPAT isomers at 5-HT(1A) sites and the putative role of these receptors in anxiety-related processes. The differential behavioural profiles of 8-OH-DPAT enantiomers suggest that racemic 8-OH-DPAT may not be an ideal tool for research on the behavioural pharmacology of 5-HT(1A) receptors.     

A9 and A10 dopamine nuclei as a site of action for effects of 8-OH-DPAT on locomotion in the rat

The 5-hydroxytryptamine (5-HT) 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was applied locally (0-5 microg bilaterally) into either the substantia nigra (A9) or the ventral tegmental area (A10) of adult male Wistar rats, and 10 min later spontaneous motor activity was observed in an open field ( approximately 0.5 m(2)) for 30 min. The rate of dopamine synthesis was estimated in neostriatal areas, the amygdala, and the prefrontal cortex, by measuring the accumulation of DOPA, following inhibition of cerebral decarboxylase by means of 3-hydroxybenzylhydrazine (NSD-1015). The A10 application of 8-OH-DPAT resulted in an increase in all aspects of spontaneous motor activity in the open field. A9 application of 8-OH-DPAT produced a stereotyped forward locomotion, characterized by a modest decrease in total horizontal activity, almost complete inhibition of rearing activity and an increase in proportion forward locomotion along the perimeter of the open-field arena. The injection of 8-OH-DPAT into the A9 was accompanied by an increased neostriatal DA rate of synthesis, whereas the A10 injection was followed by a decreased DA rate of synthesis in the amygdala and in the prefrontal cortex. It is concluded that mesencephalic dopaminergic mechanisms are involved in the stereotyped forward locomotion characteristically seen after systemic administration of the 5-HT(1A) receptor agonist 8-OH-DPAT.     

Behavioural effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in monkeys

Subcutaneous injections of a 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in monkeys induced distinct behavioural changes characterized by head weaving, hindlimb extension and upper limb fluttering. The effects were dose-dependent and were similar to the 5-HT syndrome induced in rats by 8-OH-DPAT. The 5-HT receptor antagonist, metergoline, attenuated the behavioural syndrome seen in response to 8-OH-DPAT. These results suggest that 8-OH-DPAT induces a 5-HT1A receptor-mediated behavioural syndrome in monkeys as well as in rodents.     

Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

The putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) produced in rats an increase in the number of shocks accepted in a modified Vogel's conflict test design. Subchronic pretreatment with p-chlorophenylalanine (PCPA) similarly caused release of the punished behavior. This anticonflict effect of PCPA was antagonized by both 5-hydrotryptophan and 8-OH-DPAT. Thus in naive animals 8-OH-DPAT exerting anticonflict effects acted like a 5-HT antagonist, whereas in subchronically PCPA-pretreated animals with presumably supersensitive 5-HT receptors, 8-OH-DPAT decreasing the number of accepted shocks acted like a 5-HT agonist.     

5-HT7 receptor stimulation by 8-OH-DPAT counteracts the impairing effect of 5-HT(1A) receptor stimulation on contextual learning in mice

The principal 5-HT(1A) receptor agonist 8-Hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) impairs several different types of learning. Besides 5-HT(1A) receptors, 8-OH-DPAT stimulates 5-HT(7) receptors, but it is not known whether 5-HT(7) receptors contribute to the impairments. The 5-HT(7) receptor antagonist (2R)-1-[(3-Hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl] pyrrolidine (SB-269970) was combined with 8-OH-DPAT to dissociate 5-HT(1A) from 5-HT(7) receptor-mediated effects, in the passive avoidance task for emotional learning. SB-269970 intensified impairments caused by 8-OH-DPAT. SB-269970 alone had no effect on memory performance, but moderately decreased retention under suboptimal learning conditions. These findings indicate that 5-HT(7) receptor stimulation by 8-OH-DPAT counteracts 5-HT(1A) receptor-mediated impairments in hippocampal-dependent contextual learning.     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.     

5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT_1A receptor antagonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT_1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.).We have also studied the effects of (S)-UH-301 (0.03–0.50 mg/kg i.v.) on the firing rate of single DRN5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. × 14 days). Administration of (S)UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 m1/kg/day i.p. × 14 days), control rats. Our results thus suggest that 5-HT_1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission. Since the antidepressant effect of SSRIs is critically linked to the availability of 5-HT, these findings support the notion that 5-HT_1A receptor antagonists may not only shorten the latency of onset of SSRIs in the treatment of depression, but also increase their efficacy.     

(+)-cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin: a potent and highly stereoselective 5-hydroxytryptamine receptor agonist

C1-Methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1) were synthesized and tested for central 5-HT and dopamine receptor activity by use of a biochemical test method in rats. cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin (8) was found to be a 5-HT receptor agonist. The (+)-enantiomer of 8 had a potency equal to that of 1, whereas (-)-8 and the trans isomer (+/-)-9 were inactive.     

Cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the rat: site of action and pharmacological analysis

The cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, has been investigated in the rat. Comparisons were made with clonidine, a centrally acting hypotensive agent with negligible affinity for 5-HT receptors. In conscious, spontaneously hypertensive (SH) rats, 8-OH-DPAT caused dose-related and sustained falls in blood pressure and heart rate that were unaffected by depletion of brain 5-HT by p-chlorophenylalanine. 8-OH-DPAT caused hypotension and bradycardia in anesthetized normotensive rats. In pithed rats, 8-OH-DPAT neither lowered blood pressure nor affected the cardiovascular response to spinal sympathetic stimulation or to phenylephrine. The response to 8-OH-DPAT was blocked selectively by intracisternal injection of 8-methoxy-2-(N-2-chloroethyl-N-n propyl) amino tetralin (8-MeO-CIEPAT), a putative irreversible 5-HT1A receptor antagonist, and was abolished in animals whose central monoamine transmitter stores were depleted selectively by combined treatment with DL-alpha-monofluoromethyl-dopa and dopamine. The cardiovascular response to 8-OH-DPAT was inhibited selectively by metergoline, methiothepin, and 8-MeO-CIEPAT; it was nonselectively inhibited by (+/-)-pindolol, (+/-)-cyanopindolol, buspirone, yohimbine, idazoxan, and WY 26392; and was unaffected by prazosin and cis-flupenthixol. These results establish that the cardiovascular response to 8-OH-DPAT in the rat is centrally mediated and point to the putative 5-HT1A receptor as the key site involved. An indirect link involving a catecholaminergic mechanism is suggested by the fact that alpha 2-adrenoceptor antagonists are also inhibitory despite 8-OH-DPAT having no direct agonist effects at alpha 2-adrenoceptors per se.     

Hyperinsulinemia of the genetically obese (fa/fa) rat is decreased by a low dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Changes in glycemia and insulinemia were determined in conscious lean (FA/?) and obese (fa/fa) rats after acute administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The intravenous injection of a low dose of 8-OH-DPAT (150 micrograms/kg) to lean rats rapidly promoted hyperglycemia. This modification was associated with a slight increase in insulinemia. The injection of 8-OH-DPAT markedly decreased basal hyperinsulinemia in obese rats while inducing hyperglycemia. Further evidence of the strong inhibitory effect of 8-OH-DPAT on insulin release was obtained in lean and obese rats during glucose tolerance tests. Intracerebroventricular injection of 8-OH-DPAT (45 micrograms/animal) triggered hyperglycemia and markedly decreased insulinemia in both lean and obese rats. This hypoinsulinemic effect of 8-OH-DPAT was more pronounced in the obese than in the lean animals. Measurement of the food intake elicited by 8-OH-DPAT (500 micrograms/kg s.c.) showed that the hyperphagic action of the 5-HT1A agonist was the same in FA/? and fa/fa rats. It is suggested that: (i) hyperinsulinemia of the genetically obese rat may be diminished by a low dose of 8-OH-DPAT; (ii) 5-HT1A autoreceptor-mediated regulation of serotonergic activity is not different in lean (FA/?) and obese (fa/fa) rats; (iii) 8-OH-DPAT could be of potential therapeutic use for some aspects of the pathology of type II diabetes.     

Central dopaminergic and 5-hydroxytryptaminergic effects of C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin

A number of stereochemically well defined C3-methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been synthesized, and their stereochemical characteristics have been studies by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations. The compounds were tested for activity at central 5-HT and dopamine (DA) receptors, by use of biochemical and behavioral tests in rats. In addition, the ability of the cis- and trans-8-hydroxy-3-methyl-2-(di-n-propylamino)tetralins (15 and 11) to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The stereoselectivity of the interaction of 11 and 15 with 5-HT receptors was much greater than that of 8-OH-DPAT. Observed rank order of potencies in the 5-HT1A binding assay corresponds to that in the in vivo biochemical assay.