Partial Ergoline Research Articles

The synthesis of carbon-14 labeled (R)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide hippurate. A partial ergoline with 5-HT1A agonist activity and an125I-labeled analog

Partial ergoline agonists such as (R)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz[cd]-indole-6-carboxamide (LY228729, 1a) mimic a locked conformational analog of serotonin and in fact possess potent in vitro activity as agonists of the 5-HT1A receptor. In the course of pre-clinical investigation of 1a for potential use as an anxiolytic agent, 1b was prepared in a five step synthesis from K14CN. In addition, an 125I-analog of 1a was prepared for aid in the development of a radioimmunoassay (RIA). Copyright © 2005 John Wiley & Sons, Ltd.

The synthesis of (S)-di-n-propyl-(8-isoxazol-5-yl-1,2,3,4-tetrahydronaphthalen-2-yl)amine hydrochloride and its C-14-labeled isotopomer

The partial ergoline LY228729 (1) which was a potent 5HT1A agonist has been studied clinically. Somewhat later, a related analog, (S)-di-n-propyl-(8-isoxazol-5-yl-1,2,3,4-tetrahydronaphthalen-2-yl)amine (2a) which in addition to potent 5HT1A agonist activity was a muscarinic antagonist, was chosen for clinical development for use in the treatment of irritable bowel syndrome. In the course of pre-clinical evaluation of 2a, radiolabeled material was required for ADME studies. In this paper, we have discussed the preparation of 2a and 2b (the C-14-labeled isotopomer of 2a). Copyright © 2005 John Wiley & Sons, Ltd.

Synthetic Studies toward the Partial Ergot Alkaloid LY228729, a Potent 5HT1A Receptor Agonist

Synthetic studies on LY228729 (3) afforded two innovative approaches for the construction of this class of partial ergoline 5HT1a receptor agonists. The first synthesis is based upon a diastereoselective epoxidation of racemic olefin 5, followed by ring opening and covalent resolution to furnish the key amino alcohol 8. Aziridination of amino alcohol 8, with subsequent tandem hydrogenolysis of the benzylic aziridine and auxiliary bonds, provided access to the optically active primary amine 13. A novel catalytic carboxamidation reaction installed the requisite side chain. Alternatively, the chiral pool was drawn upon for the single stereogenic center by virtue of l-tryptophan, albeit by a more circuitous route than expected. l-Tryptophan was differentially protected and reduced to the indoline diastereomers 26a,b which were separated by fractional crystallization. The two indoline diastereoisomers were independently cyclized by a Friedel−Crafts protocol, which under thermodynamic control afforded enantiomeric ketones 30a. The ketone was deoxygenated with a two-step reduction protocol to intersect the initial route and complete the second total synthesis. The two routes offer complementary access to this exciting class of partial ergot alkaloids.

Application of Palladium(0)-Catalyzed Processes to the Synthesis of Oxazole-Containing Partial Ergot Alkaloids

Syntheses of the potent 5-HT1A agonists 2 and 3 were accomplished in several steps from the 6-iodo partial ergoline alkaloid 8. Disparate tactics available for construction of differentially substituted oxazoles led to the development of new and general methodology critical to the efficient preparations of 2 and 3. A novel palladium(0)- and copper(I)-cocatalyzed cyanation reaction provided efficient access to the nitrile 10, a key intermediate in the synthesis of 2. A palladium(0)-catalyzed cross-coupling reaction of 16 with oxazol-2-ylzinc chloride formed the potent 5-HT1A agonist 3.

Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)

ChemInform Abstract: Substituted 5‐Amino‐4,5,6,7‐tetrahydroindazoles as Partial Ergoline Structures with Dopaminergic Activity.

AbstractThe 5‐aminotetrahydroindazoles (IV) or (XII) are prepared by the reduction of the corresponding amide precursors (III) and (XI) respectively.

6-Substituted tricyclic partial ergoline compounds are selective and potent 5-hydroxytryptamine 1A receptor agents

A series of 6 tricyclic partial ergoline derivatives was analyzed using radioligand binding assays. Four agents (LY 178210, LY 254089, LY 197205, and LY 197206) display high affinity (K i 1.3 nM) for 5-hydroxytryptamine 1A (5-HT 1A) receptor binding sites labeled by [ 3H] 8-hydroxy-2-(d1-n-propylamino) t tetralin (8-OH-DPAT) and display ⩾ 150 fold selectivity for the 5-HT 1A over the 5-HT 1D receptor binding site. The most potent agent investigated, LY 178210, is essentially inactive (K i > 1500 nM) at a total of 12 other neurotransmitter receptor binding sites in the brain. Using a forskolin-stimulated adenylate cyclase assay as a model of 5-HT 1A receptor function, LY 178210 was found to display partial agonist activity which was blocked by 10 −5 M (-) pindolol. These data indicate that LY 178210 is a potent and selective 5-HT 1A receptor partial agonist.

Substituted 5-amino-4,5,6,7-tetrahydroindazoles as partial ergoline structures with dopaminergic activity

Two series of tetrahydroindazoles were synthesized and evaluated for dopaminergic activity. A number of these partial ergoline analogues possess substituents that could mimic the C-8 substituent of the dopaminergic ergolines. Of the unsymmetrically substituted amine series 7a-k, the (monopropylamino)tetrahydroindazole 7b was most interesting as it was found to selectively activate the dopamine (DA) autoreceptor at a dose of 5 mg/kg in rats. The disubstituted amines 7g-k had significant DA postsynaptic activity as measured by increases of serum corticosterone levels in rats. The 6-substituted-5-aminotetrahydroindazoles 10a-d were found to possess only marginal dopaminergic activity.

Synthesis and biological evaluation of 3-(2-aminoethyl)pyrrole derivatives.

AbstractThe ergolines are an important class of dopamine receptor agonists1), and the identification of their dopaminergic pharmacophore has been sought as a means of developing “purer” agonists related to these structures2).Ergolines combine a phenethylamine and a pyrroleethylamine moiety, both of which have been proposed as the dopaminergic pharmacophores of the molecules3,4). Support for these postulates is the fact that certain simplified partial ergoline structures5,6) show potent dopamine agonist activities.The simple 3‐(2‐aminoethyl)pyrrole was also synthesized6) but it was found inert as a dopamine receptor agonist. This inactivity was rationalized on the basis that this primary amino compound is rapidly destroyed in vivo by monoamine oxidases6).

Elevation of acetylcholine levels in striatum of rat brain by LY163502, trans−(−)−5,5a,6,7,8,9a,10-octahydro-6-propylpyrimido〈4,5−g〉quinolin-2- amine dihydrochloride, a potent and stereospecific dopamine (D 2) agonist

LY163502, a partial ergoline and a trans-levorotatory enantiomer, does not stimulate adenylate cyclase in striatal membranes but inhibits 50% binding of 3H-apomorphine, 3H-pergolide and 3H-spiperone at 10, 13 and 151 nM (IC 50), respectively. The racemic mixture (LY137157) is less effective, with 3, 2.7 and 1.4 times higher IC 50 values, respectively, whereas the dextrorotatory isomer (LY175877) is inactive. LY163502 inhibits binding of 3H-clonidine with an IC 50 value of 2600 nM, but not the binding of 3H-WB4101, 3H-dihydroalprenolol, 3H-serotonin, 3H-quinuclidinyl benzilate and 3H-pyramilamine or the uptake of serotonin, norepinephrine or dopamine, suggesting selective affinity toward dopamine receptors in vitro . Both LY163502 and LY137157 elevate striatal acetylcholine (Ach) levels. The elevation of Ach levels by LY163502 is reversed by dopamine antagonists haloperidol, cis -flupenthixol and metoclopramide. Therefore, the levorotatory enantiomer exhibits pharmacology of a D 2 type of dopamine agonist.

Pergolide elevation of MHPG sulphate concentration in rat hypothalamus blocked by spiperone and mimicked by other dopamine agonists

Pergolide increased the concentration of MHPG sulphate (3-methoxy-4-hydroxy-phenylethylene glycol sulphate) in rat hypothalamus, and the increase was prevented by pretreatment with spiperone, a dopamine antagonist. An increase in hypothalamic MHPG sulphate concentration similar to that caused by pergolide was found after injection of quinpirole, a 'partial ergoline' that is a selective D2 agonist not affecting alpha-adrenoceptors, and by (-)-N-propylnorapomorphine, a dopamine agonist not related to the ergolines. Although the increase in MHPG sulphate concentration produced by pergolide had earlier been assumed to result from blockage of alpha-adrenoceptors, the present data indicate that it is an effect produced by dopamine D2 receptor stimulation.

No evidence for the involvement of histamine (H 1 or H 2) receptors in the hypotension and presynaptic inhibition of sympathetic nerve function caused by LY-141865 in dogs

LY-141865, a partial ergoline, caused hypotension, bradycardia and significant impairment of cardioacceleration elicited during stimulation of cardiac sympathetic nerves. These cardiovascular actions of LY-141865 were not affected either by the H 1-receptor antagonist mepyramine or the H 2-receptor antagonist cimetidine. The dopamine receptor antagonist sulpiride significantly reduced the hypotensive, bradycardic and presynaptic inhibitory actions of LY-141865. These results show that while dopamine receptor activation is responsible for the hypotension and presynaptic inhibition of sympathetic nerve function caused by LY-141865, histamine (H 1- or H 2-) receptors do not play any role in these actions of the compound.

Guanine nucleotides reveal differential actions of ergot derivatives at D-2 receptors labelled by [ 3H]spiperone in striatal homogenates

The specific binding of [3H]spiperone (35 pM), as defined by the D-2 antagonist sulpiride, was potently displaced by ergot derivatives of both the ergoline and ergopeptine type, and by dopamine agonists and antagonists. The potency of the ergot derivatives ranged widely from an IC50 value of 3 nM for bromocriptine to a value of 1000 nM for the partial ergoline, LY-141865. GTP and its stable analogue, guanyl-5'-yl-imidodiphosphate (Gpp(NH)p), did not affect the affinity (100 pM) or density (30 pmol/g wet wt) of [3H]spiperone binding sites, but did decrease the potency of a number of ergoline compounds including pergolide, lergotrile and LY-141865, as well as dopamine agonists to displace [3H]spiperone binding. The affinities of the ergopeptines, bromocriptine and dihydroergocryptine, and of the isolysergic acid ergoline, lisuride, and dopamine antagonists were unaltered by the presence of guanine nucleotides. The effect was specific for guanine nucleotides, with near maximal effects on agonist affinity observed in the presence of a 100 microM concentration of nucleotide. The relative decrease in affinity found in the presence of GTP or Gpp(NH)p varied widely for individual ergot derivatives and dopamine agonists. The largest decrease was seen with dopamine itself, and agonists such as the tetralins and with LY-141865. Many ergolines had shifts in potency between those seen for agonists and antagonists, suggesting a partial agonist action at D-2 receptors. Guanine nucleotide sensitivity may represent a valuable in vitro method for studying the agonist/antagonist properties of dopaminergic drugs, such as the semi-synthetic ergoline compounds.

Interactions of a partial ergoline with dopamine receptors in vivo and in vitro.

Interactions of a partial ergoline with dopamine receptors in vivo and in vitro.

Therapeutic potentials of centrally acting dopamine and alpha 2-adrenoreceptor agonists.

The antiparkinsonian activity of several dopamine agonists was investigated in an animal model and clinically in parkinsonian patients. The semisynthetic ergoline, pergolide, the partial ergoline, LY 141865 and the 8-alpha-aminoergoline, CU 32-085 were found to be effective antitremor agents in monkeys with ventromedial tegmental lesions. The administration of pergolide or LY 141865 results in a relief of tremor with a concomitant occurrence of severe abnormal involuntary movements, while the administration of CU 32-085 results in a relief of tremor with the occurrence of only minor abnormal involuntary movements. Clinical studies have revealed that pergolide is an effective drug in patients with advanced Parkinson's disease, and it reduces the "on-off" phenomena. The possible regulation of dopamine neurotransmission by the norepinephrine neuronal systems was reviewed. Preliminary data suggest that clonidine may interact with presynaptic dopamine receptors.

Stimulation of pre- and postsynaptic dopamine receptors by an ergoline and by a partial ergoline

The capacity of the ergoline, pergolide, and of the partial ergoline, LY 141865, to stimulate pre- and postsynaptic dopamine (DA) receptors was investigated. Binding studies have revealed that pergolide has a high affinity, while the partial ergoline, LY 141865, has a low affinity for the postsynaptic striatal DA receptors in vitro. Two behavioral animal models were used to assess the DA agonist potencies of these compounds for the postsynaptic DA receptors in vivo. Pergolide induced turning behavior in rats with 6-hydroxydopamine (6-OH-DA) lesions, and relief of tremor in monkeys with ventromedial tegmental lesions, at a lower dose and for a longer duration than LY 141865. An in vivo and an in vitro biochemical test was use to measure the ability of these compounds to stimulate presynaptic DA receptors. In the in vitro test, pergolide and LY 141865 were found to have low inhibitory activity for synaptosomal tyrosine hydroxylase, while in the in vivo test, both drugs were effective even in low doses in reversing the gamma-butyrolactone elicited increased accumulation of striatal DOPA. These results suggest that pergolide has a high affinity for pre- and postsynaptic DA receptors, while its partial ergoline analogue has a high affinity for the presynaptic, but not for the postsynaptic DA receptors. The data also suggest that dopamine synthesis in vitro and in vivo may be regulated by different presynaptic DA receptors.