5-HT1B D RECEPTOR ANTAGONISTS

1. 5-Hydroxytryptamine 1B (5-HT1B, formerly designated 5-HT1D beta) an d 5-hydroxytryptamine-1D (5-HT1D, formerly designated 5-HT1D alpha) re ceptors are distinct molecular entities that mediate serotonergic neur otransmission. Both are G-protein-coupled receptors without introns in their coding region, negatively coupled to adenylate cyclase; their p recise function in human beings remains to be defined, In brain, they are highly enriched in the globus pallidus and the substantia nigra. 2 . Presynaptic 5-HT1B/D receptors take part in the control of the relea se not only of 5-HT itself, but also of other neurotransmitters-for ex ample, acetylcholine, glutamate, dopamine, noradrenaline and gamma-ami nobutyric acid. Selective blockade of central 5-HT1B/D autoreceptors s hould facilitate 5-HT neurotransmission and may offer a novel approach to antidepressant therapy. Other 5-HT1B/D receptors are located posts ynaptically; those receptors may be supersensitive in the pathophysiol ogy of obsessive-compulsive disorder and may be a potential target for its treatment. 3. Few if any ligands show selectivity for 5 HT1B or 5 -HT1D receptors or both. Most pharmacological studies have been perfor med with nonselective antagonists-for example, metergoline, 1-naphthyl piperazine, methiothepin, ketanserin and ritanserin. Recently, a never series of benzanilides have been reported as the first examples of se lective 5-HT1B/D receptor antagonists. GR 127935, a representative com pound of this series, displays mixed agonist antagonist properties bot h in vitro and in vivo. It induces upon systemic administration in the guinea pig either an opposite (decrease) effect or a small increase ( 65%, 5 mg/kg) in the concentration of cortical extracellular 5-HT comp ared with fiuoxetine (218%, 10 mg/kg). The importance of blockade of 5 -HT1B/D receptors in the raphe region, their possible interaction with 5-HT1A receptors, and consequent inhibition of 5-HT release in termin al 5-HT1B/D receptor containing regions are discussed. 4. To find out whether the available so-called 5-HT1B/D receptor antagonists are inde ed antagonists and not partial agonists, efficacy was measured at reco mbinant human 5-HT1B and 5-HT1D receptor sites by using a [S-35]-GTP g amma S binding assay to membrane preparations of stably transfected ra t C6-glial cell lines. Metergoline and the selective 5-HT1B/D receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic a ctivity (43% to 69%) at the 5-HT1D receptor subtype, whereas the nonse lective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsi c activity at both receptor subtypes. In contrast, the nonserective li gands methiothepin, ketanserin and ritanserin are inverse agonists bec ause they displayed negative efficacy (-14% to -28%). Differential blo ckade of 5-HT1B/D receptors by neutral antagonists and inverse agonist s is discussed in relation to the 5-HT tone on 5-HT1B/D receptors. 5. It can be concluded that 5-HT1B/D receptor ligands modulate 5-HT neuro transmission through a terminal 5-HT1B/D receptor. Future work should be directed toward the identification of selective 5-HT1B and 5-HT1D r eceptor ligands that display either neutral antagonist or inverse agon ist properties to evaluate the therapeutic potential of 5-HT1B/D recep tor blockade. (C) 1991 Elsevier Science Inc.