Ergoline derivatives: receptor affinity and selectivity.

Ergot comprises a group of indole alkaloids which are predominantly found in various species of the ascomycete Claviceps. In pharmacopoeias, the sclerotia of Claviceps purpurea (Fr.) Tulasne parasitizing on rye, Secale cereale L., are designed as ergot or Secale cornutum. Now, the term ergot is used in a broader sense to describe the sclerotia of various Claviceps species growing on different host plants or their saprophytic mycelia. Due to their many fascinating features, there is a continuing and extensive interest in these secondary metabolites. Thus, the chemistry of ergot alkaloids and derivatives has presented many challenges to organic chemists. The ergot alkaloids and derivatives have attracted great interest for their broad spectrum of pharmacological action that includes central, neurohumoral and peripheral effects. These are mainly responses mediated by noradrenaline, serotonin, or dopamine receptors. No other group of natural products exhibits such a wide spectrum of biological action. For this reason, ergot has been termed a veritable treasure house of pharmacological constituents'. Moreover, ergot alkaloids have been an important stimulus in the development of new drugs by providing structural prototypes of molecules with pronounced pharmacological activities. This concise review, moving from the experience of our group in Pharmacia & Upjohn, will briefly mention the most representative ergoline derivatives featured in the literature. Our work in this field originated compounds with quite different pharmacological activities. In fact, by continuous modification of the same main template structure, the ergoline skeleton, it ultimately led to the development of new dopaminergic agents and to the identification of new series of serotonergic agents.

Synthesis and antihypertensive activity of 2,4-dioxoimidazolidin-1-yl and perhydro-2,4-dioxopyrimidin-1-yl ergoline derivatives.

The synthesis and antihypertensive activity of a series of 2,4-dioxoimidazolidin-1-yl and perhydro-2,4-dioxopyrimidin-1-yl ergoline derivatives are reported. The oral antihypertensive activity was studied in spontaneously hypertensive rats (SHRs) by measuring systolic blood pressure by an indirect tail-cuff method at different times after treatment. The prolactin lowering activity (indirectly measured by the nidation test) in rats and the oral acute toxicity in mice were also studied. The results of this study revealed potent antihypertensive ergoline derivatives devoid of side-effects related to the dopaminergic stimulation and the importance of the delta 9,10 double bond for conferring high potency within these compounds.

Synthesis and in vitro and in vivo evaluation of dopaminergic ergoline derivatives.

A series of ergoline-amides was synthesised in the discovery of new dopaminomimetic agents. Several compounds exhibited in vivo high prolactin lowering activity (indirectly measured by the nidation test) in rats. For the most active, the potential anti-Parkinson activity was evaluated by observation of the contralateral turning behaviour in 6-OH-DA lesioned rats. The acute toxicity by oral route in mice was also studied.

Serotonergic ergoline derivatives.

Novel classes of 13- and 14-tertbutyl-ergoline derivatives were prepared, and characterised in vitro for their affinity for adrenergic, dopaminergic and serotonergic binding sites. This study particularly examines the importance of the presence and the position of the tert-butyl group in conferring either significant 5-HT1A or 5-HT2 affinity and selectivity respectively.

Disposition and urinary metabolic pattern of cabergoline, a potent dopaminergic agonist, in rat, monkey and man.

1. The disposition and urinary metabolic pattern of 14C-cabergoline was studied in rat, monkey and man after oral administration of the labelled drug. 2. In all species radioactivity was mainly excreted in faeces, with urinary excretion accounting for 11, 13 and 22% of the dose in rat, monkey and man, respectively. 3. After oral treatment, biliary excretion of radioactivity in rat accounted for 19% of the dose within 24 h. 4. Unchanged drug in 0-24-h urine samples of rat, monkey and man amounted to 20, 9 and 10% of urinary radioactivity, respectively. In the 24-72-h urine samples of all species the relative percentage of unchanged drug increased compared with that measured in the 0-24-h urine. 5. The main metabolite was the acid derivative (FCE 21589), which in 0-24-h urine samples of rat, monkey and man accounted for 30, 21 and 41% of urinary radioactivity, respectively. 6. Other metabolites identified in urine of all species resulted from hydrolysis of the urea moiety, the loss of the 3-dimethylaminopropyl group and the deallylation of the piperidine nitrogen.

FCE 23884, substrate-dependent interaction with the dopaminergic system. I. Preclinical behavioral studies.

FCE 23884, a newly synthetized ergoline derivative, shows dopamine (DA) agonist or antagonist properties depending on the functional state of the biological substrate. The compound behaves as a full DA antagonist in normal animals, but shows full agonist properties in denervated models in the same dose range. In normal animals, FCE 23884 impairs Sidmans avoidance in rats, reduces spontaneous locomotion in mice and monkeys and antagonizes apomorphine-induced climbing behavior in mice, yawning in rats, emesis in dogs and amphetamine-induced toxicity in grouped mice. After experimental procedures resulting in severe DA depletion, FCE 23884 behaves as a powerful DA-agonist mainly at D-1 receptors. FCE 23884 induces contralateral turning behavior in 6-hydroxydopamine-lesioned rats and reverses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced akinesia in monkeys and reserpine-induced hypokinesia in mice. These results indicate that the antagonist or agonist activity of FCE 23884 is substrate-dependent and mostly related to the presence or absence of DA. This leads to the apparently paradoxical suggestion that the compound could be useful both in psychotic states and extrapyramidal diseases, i.e., in clinical conditions characterized by either excessive or impaired DAergic neurotransmission.

FCE 23884, substrate-dependent interaction with the dopaminergic system. II. Preclinical biochemical studies.

The effects of FCE 23884 [4-(9,10-didehydro-6-methylergolin-8 beta-yl) methyl-piperazine-2,6-dione] were examined using a variety of biochemical methods. In vitro assays showed that FCE 23884 bound to D-2, alpha-2 and 5-hydroxytryptamine1A sites with Ki values of 6.5, 4.0 and 4.0 nM, respectively. The affinity for D-1 and S-2 receptors was moderate (submicromolar range) and slight or negligible for alpha-1, cholinergic and sigma receptors. In normal rats, FCE 23884 accelerated markedly dopamine (DA) turnover in the neostriatum and nucleus accumbens as indicated by the increased ratios of dihydroxphenyl acetic acid/DA and homovanillic acid/DA. The compound enhanced DA synthesis and utilization rate. After gamma-butyrolactone treatment, a model to study DA autoreceptors function, FCE 23884 almost antagonized completely the gamma-butyrolactone reversal induced by apomorphine on l-dihydroxyphenylalanine accumulation in the two brain areas. In addition, FCE 23884 induced a rapid 20-fold increase of serum prolactin confirming its DA antagonistic profile in normal rats. In contrast with these antidopaminergic properties, FCE 23884 consistently stimulated basal adenylate cyclase activity in vitro (ED50 = 0.6 microM) and elicited a rapid increase of cyclic AMP formation in the neostriatum of normal (35%) and reserpinized (82%) rats in vivo. Furthermore in this last condition both the DA turnover and synthesis rate in the neostriatum and nucleus accumbens decreased after treatment with FCE 23884. These neurochemical data support the behavioral studies indicating that FCE 23884 possesses mixed DA antagonist and agonist properties depending on the experimental conditions, the distinguishing factor being presence or absence of DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive ergoline derivatives.

Novel ergolines were synthesized and screened in spontaneous hypertensive rats (SHR) with the aim of finding a new class of ergot related antihypertensives. Their prolactin inhibitory effect (measured as nidation inhibition in rats), acute toxicity (LD50) and interference with CNS function (Irwin test) were also evaluated as a measure of selectivity and safety. Modification of the C8 side-chain enhanced antihypertensive activity selectively, while the introduction of substituents in other positions of the ergoline skeleton generally yielded unfavourable results, either by decreasing selectivity or by increasing toxicity.

Antihypertensive ergolinepropionamides.

The synthesis and the antihypertensive activity in rats of a series of 6-methylergolin-8 beta-yl-propionic acid derivatives are reported. The prolactin lowering activity (nidation inhibition test) in rats and the acute toxicity in mice were also studied as a measure of the specificity and safety of the potential antihypertensive compounds. From the structure-activity considerations reported here it is clear how modifications at the C8 side chain can improve the selectivity of the antihypertensive effects, whilst introducing substituents in other positions of the ergoline skeleton afforded unfavourable results in this respect. Compound 5, namely 2(R,S)-cyano-3-(6-methylergolin-8 beta-yl)-propionamide, emerged as the most interesting antihypertensive derivative.