S.Z. Langer, I. Angel and H. Schoemaker,     Synthélabo Recherche (L.E.R.S.), 58 rue de la Glacière, 75013 Paris, France

ABSTRACT

During the last twenty years, the concept that noradrenaline can regulate its own release through an action on presynaptic autoreceptors, has been confirmed and extended to several neurotransmitters in the periphery and in the central nervous system. In addition, many nerve terminals possess presynaptic heteroreceptors which can be acted upon by transmitters released from adjacent terminals, by cotransmitter neuropeptides or by locally produced or blood-borne endocoids to either inhibit or facilitate transmitter release. In the noradrenergic system, the concept of presynaptic modulation of transmitter release developped in parallel with pharmacological evidence for the existence of α2-and α2-adrenoceptor subtypes. In the meanwhile three different α2-adrenoceptor clones were identified by molecular biologists that may correspond to pharmacologically different subtypes of α2-adrenoceptors. The heterogeneity of presynaptic release-modulating α2-adrenoceptors may offer the opportunity of developping selective drugs with novel and useful therapeutic properties.

KEYWORDS

Presynaptic autoreceptors

Transmitter release

Alpha adrenoceptor subtypes

Presynaptic heteroreceptors

Noradrenaline

Neuropeptide cotransmitters

Introduction

Neurotransmitters can regulate their own release through an action on inhibitory autoreceptors located on the synaptic nerve terminal (for recent reviews see Langer and Lehmann, 1988; Starke et al, 1989). The physiological role of presynaptic inhibitory autoreceptors was first established for noradrenaline in the peripheral nervous system through the demonstration of a negative feed-back mechanism through which this transmitter can modulate its own release (Langer, 1974). The pharmacological possibilities for intervention through selective agonists, partial agonists or antagonists acting on presynaptic, release modulating receptors, resulted from the characterization of the autoreceptor subtype for each of the neurotransmitters. In addition to presynaptic autoreceptors, many nerve terminals possess presynaptic heteroreceptors that are sensitive to endogenous mediators other than the neuron’s own transmitter. Activation of these terminal presynaptic heteroreceptors can either inhibit or facilitate the release of a neurotransmitter. In contrast to presynaptic terminal autoreceptors, the physiological role of presynaptic heteroreceptors remains to be established. Nevertheless, selective agonists or partial agonists should be expected to produce pharmacological effects through the activation of presynaptic heteroreceptors even if these receptors are not involved in a physiologically relevant mechanism modulating transmitter release.

While it is well established that the presynaptic autoreceptor that regulates noradrenaline release corresponds to the α2-subtype (Langer, 1974, 1981), recent molecular biology and receptor binding studies indicate that the α2-adrenoceptor is expressed as three distinct receptor subtypes (Bylund 1988, Harrison et al. 1991). The functional relevance of the three cloned α2-adrenoceptor subtypes is still an open question.

One example of a peripheral neuroeffector junction where α2-adrenoceptors are present both pre-and-postsynaptically is offered by the insulin secreting β-cells of the pancreas. The present article reports the pharmacological profile of SL 84.0418, a pyrrolo-indole derivative with high selectivity for α2-adrenoceptors in the periphery (Langer et al. 1990; Langer and Angel, 1991). This α2-adrenoceptor antagonist is at present being tested in man as a novel therapeutic approach for the treatment of type Π or non-insulin dependent diabetes mellitus (NIDDM).

Materials and Methods

The twitch response of the isolated rat vas deferens was employed to study drug effects at presynaptic α2-adrenoceptors as described by Hicks et al (1985) and the rabbit pulmonary artery was used to determine postsynaptic α2-adrenoceptor antagonism in-vitro according to Schoemaker et al (1989). Drug effects on α2-adrenoceptor agonist-induced hyperglycemia were studied according to Angel et al (1990).

Results

The pyrrolo-indole derivative SL 84.0418 is a potent, competitive antagonist of the inhibition by clonidine of the twitch response of the rat vas deferens and the pA2 is similar to that obtained with idazoxan (Table 1). SL 84.0418 has a chiral center and is a racemic mixture of two enantiomers, SL 86.0715 ((+) enantiomer) and SL 86.0714 ((-) enantiomer). The (+) enantiomer, SL 86.0715 is at least 100-fold more potent than the (-) enantiomer, SL 86.0714 (Table 1).

As shown in table 1, SL 84.0418 and its (+) enantiomer, SL 86.0715 are considerably less potent at α,-adrenoceptors, and they possess a selectivity ratio of more than 1000 when their α2-and α1-adrenoceptor antagonist properties are compared under in-vitro conditions.

As shown in Table 2, SL 84.0418 antagonized in a dose-dependent manner the hyperglycemia induced by UK 14304 in mice. This α2-adrenoceptor blocking property resides in the active enantiomer SL 86.0715 (table 2) while SL 86.0714 was much less active in this test (table 2). Consequently both in-vitro and in-vivo SL 84.0418 and 86.0715 elicit α2-adrenoceptor antagonist effects.

Discussion

The novel α2-adrenoceptor antagonist SL 84.0418 and its active enantiomer SL 86.0715 represent the most selective compound so far reported in this pharmacological class. From our experimental models it appears that SL 84.0418 possesses similar potency as an antagonist of presynaptic as well as postsynaptic α2-adrenoceptors. For exemple, in the in situ blood perfused dog pancreas SL 84.0418 enhances the release of endogenous noradrenaline during sympathetic nerve stimulation in the same range of doses in which it antagonizes the inhibition of insulin release induced by activation of postsynaptic α2-adrenoceptors (Duval et al., 1991). In contrast to idazoxan, which blocks both central and peripheral α2-adrenoceptors, upon oral administration, SL 84.0418 antagonizes preferentially the responses induced by activation of peripheral α2-adrenoceptors (Langer and Angel, 1991; Angel et al. 1991b). Further to the antagonism of alpha-2 agonist induced hyperglycemia, in the monkey the oral administration of SL 84.0418 or SL 86.0715 reduce in a dose-dependent manner the hyperglycemia induced by an oral glucose load (Hulbron et al, 1990). Similar results were obtained in man, at doses devoid of cardiovascular and other side effects (Bergougnan et al. 1990).

The selectivity of SL 84.0418 for the three reported subtypes of α2-adrenoceptors (Harrison et al. 1991) remains to be established, and it would be of interest to characterize the subtype of α2-adrenoceptor which modulates presynaptically noradrenaline release and the postsynaptic α2-adrenoceptor associated with the inhibition of insulin release in the pancreas.

Conclusions

The development of novel and selective compounds acting preferentially as α2-adrenoceptor antagonists may offer novel therapeutic approaches in the treatment of several diseases. The selective α2-adrenoceptor antagonist SL 84.0418 is a potential drug for the treatment of type Π non insulin dependent diabetes. Different pharmacological interventions are possible at the level of presynaptic release modulating receptors. These compounds may become important pharmacological tools and most significantly, novel and useful therapeutic agents.

Acknowledgement

The authors wish to thank Miss Anny Sebbah for preparing the manuscript.

References