6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as Potent and Orally Active Serotonin 5-HT1A Receptor Agonists

Stjernlöf, Peter; Nilsson, Jonas; Åndersson, Bengt; Lagerkvist, Sören; Svensson, Kjell; Ekman, Agneta; Carlsson, Arvid; Wikström, Håkan

doi:10.1021/jm00046a010

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…Statistical comparisons: reserpine controls (striped columns) vs. NaCl (filled columns), and vs. corresponding TFMPPB-OH-DPAT (shadowed columns)-treated groups (t-test), tP < 0.01, and IrP c: 0.01, respectively. yielding EC50 and 95% confidence limits (CL), as described by Stjernlof et al (1994). The half-maximal 5-HT synthesis-reducing effect of TFMPP was obtained at 0.39 pM (CL 0.28-0.57).…”

Section: Reserpinementioning

confidence: 91%

Evidence for 5‐HT autoreceptor‐mediated, nerve impulse‐independent, control of 5‐HT synthesis in the rat brain

Stephan

Suchowski

Galloway

1995

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To gain further insight into the operation of 5-HT autoreceptor-mediated feedback control of 5-HT biosynthesis in serotonergic nerve terminal areas, the effect of the 5-HT1B and the 5-HT1A receptor agonists, TFMPP and 8-OH-DPAT, respectively, were investigated in the rat central nervous system (CNS) using in vivo and in vitro neurochemical approaches. TFMPP suppressed 5-HT synthesis (5-HTP accumulation after decarboxylase inhibition) both in vivo and in vitro. In vivo, the 5-HT synthesis-suppressing effect of the drug (3.0 mg/kg, s.c.) proved resistant to either acute hemitransection or reserpine (5 mg/kg, i.p.; 90 min before) pretreatment. In vitro, in cortical, hippocampal and striatal slice preparations, TFMPP (0.1-10 microM) decreased 5-HT synthesis under basal and stimulated (30 mM K+) conditions, an effect which was unaltered by prior in vivo reserpine-induced 5-HT depletion but was attenuated in the presence of 5-HT1B receptor antagonists such as methiothepin, cyanopindolol or propranolol. The 8-OH-DPAT (0.1 mg/kg, s.c.)-induced decrease of 5-HT synthesis in vivo was abolished by hemitransection but resistant to acute reserpine pretreatment; 8-OH-DPAT (10 microM) did not decrease 5-HT synthesis in vitro. In conclusion, the present study confirms the importance of 5-HT autoreceptors in the feedback control of nerve terminal 5-HT biosynthesis. Specifically, our data indicate: (1) that the reduction of rat brain 5-HT synthesis after TFMPP is mediated by 5-HT1B autoreceptors located on the serotonergic axon terminals, and (2) that the effect is directly mediated and occurs independently of 5-HT neuronal firing and intact monoamine stores.

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Section: Reserpinementioning

confidence: 91%

Evidence for 5‐HT autoreceptor‐mediated, nerve impulse‐independent, control of 5‐HT synthesis in the rat brain

Stephan

Suchowski

Galloway

1995

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“…For analytical purposes the mixed fraction was subjected to another chromatography (hexane/ ethyl acetate, 4:1-1:1), giving some pure fractions of the three possible isomers eluting in the named order. 17a: NMR (300 MHz, CDCls) d 0.95 (t, 3H), 1.20 (t, 3H), 1.65 (oct, 2H), 2.0 (m, 2H), 2.40 (q, 2H), 2.8-3.S (m, 6H), 4.0 (m, 0.25H), 4.45 (sept, 0.75H), 7.08 (dd (0.75) and dd (0.25), J = 8.4, 2.2 Hz, 1H), 7.47 (dd, J = 8.1, 2.2 Hz, 0.75H), 7.53 NMR (300 MHz, CDCls) d 0.95 (t, 3H), 1.20 (t, 3H), 1.60 (sxt, 2H), 2.0 (sxt, 2H), 2.35 (q, 2H), 2.S-3.3 (m, 6H), 4.03 (m, 0.25H), 4.45 (sept, 0.75H), 7.03 (quintet, 1H), 7.17 (m, 1H); MS m/e 308 (M+, 0.2), 116 (100), 176 (37), 57 (35), 223 (18). jV-(7-Amino-6-fluoro-l,2,3,4-tetrahydronaphthalen-2-yD-JV-propylpropionamide (18).…”

Section: Methodsmentioning

confidence: 99%

“…[3][4][5][6] In a series of articles, the tricyclic ring systems 8-(dialkylamino)-6,7,8,9-tetrahydrobenz[e]-and -[g]indoles were examined for their serotonergic activity. [7][8][9] This was initiated by the finding by Wikstrom et al8 that the unsubstituted 8-( dimethyl amino )-6,7,8,9-tetrahydrobenz[e]indole (3) displayed serotonergic activity at 5-HTia receptors, beside its previously reported dopaminergic activity.10 A subsequent paper from our group showed that the IV,IV-dipropyl analog of 3 (compound 4) is a potent 5-HTia agonist, although not selective with regard to dopamine D2 receptors. 9 In the same paper it was shown that introduction of a formyl group in the 1-position (compound 5 and enantiomers) altered the selectivity toward 5-HTia yielding one of the most potent 5-HTia agonists reported.…”

Section: Introductionmentioning

confidence: 99%

“…In a subsequent paper, Romero et al showed that the corresponding 2-cyano compound 6 was equipotent to 5, whereas the 2-carboxamide 7 was not as potent.11 These findings resulted in a further analog investigation where the 1-cyano (8), 1-chloro (9), and 1,1,1-trifluoroethyl (10) analogs were tested and compared to compounds 5 and 6. 7 The high potency of both cyano derivatives 6 and 8 and their enantiomers raised some questions concerning the drug-5-HTia receptor interaction. Compounds 9 and 10 were less potent.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Activity Relationships in the 8-Amino-6,7,8,9-tetrahydro-3H-benz[e]indole Ring System. Part 1: Effects of Substituents in the Aromatic System on Serotonin and Dopamine Receptor Subtypes

Stjernlöf¹,

Ennis²,

Lo³

et al. 1995

J. Med. Chem.

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A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A against 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D2, and D3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.

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“…Biochemistry. The biochemical experiments and the determinations of DOPA and 5-HTP by means of HPLC with electrochemical detection were performed as previously described.36•37 ED50 values were calculated by fitting a sigmoidal curve to the dose responses according to Stjernlof et al 38 The ED50 values are given in umol/kg. From these graphs, the doses of the drug yielding a half-maximal decrease (ED50 value) of the 5-HTP (the maximal effects, expressed as percent of controls, were as follows: limbic system, striatum, and the hemispheres = 50%) and the DOPA (the maximal effects, expressed as percent of controls, were as follows: limbic system = 35%, striatum = 20%, and the hemispheres = 50%) levels were estimated separately (Table 2).…”

Section: (R)-(+)-7-[[(trifluoromethyl)sulfonyl]oxy]-2-(«-propylamino)...mentioning

confidence: 99%

Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of Monopropyl Analogs of 5-, 7-, and 8-[[(Trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: Central Dopamine and Serotonin Receptor Activity

Sonesson

Barf²,

Nilsson³

et al. 1995

J. Med. Chem.

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In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.

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6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as Potent and Orally Active Serotonin 5-HT1A Receptor Agonists

Cited by 17 publications

References 31 publications

Evidence for 5‐HT autoreceptor‐mediated, nerve impulse‐independent, control of 5‐HT synthesis in the rat brain

Evidence for 5‐HT autoreceptor‐mediated, nerve impulse‐independent, control of 5‐HT synthesis in the rat brain

Structure-Activity Relationships in the 8-Amino-6,7,8,9-tetrahydro-3H-benz[e]indole Ring System. Part 1: Effects of Substituents in the Aromatic System on Serotonin and Dopamine Receptor Subtypes

Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of Monopropyl Analogs of 5-, 7-, and 8-[[(Trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: Central Dopamine and Serotonin Receptor Activity

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