CP 93129 dihydrochloride

Modulation of neurotransmission by GPCRs is dependent upon the microarchitecture of the primed vesicle complex.[Pubmed:24381287]

J Neurosci. 2014 Jan 1;34(1):260-74.

G(i/o)-protein-coupled receptors (GPCRs) ubiquitously inhibit neurotransmission, principally via Gbetagamma, which acts via a number of possible effectors. GPCR effector specificity has traditionally been attributed to Galpha, based on Galpha's preferential effector targeting in vitro compared with Gbetagamma's promiscuous targeting of various effectors. In synapses, however, Gbetagamma clearly targets unique effectors in a receptor-dependent way to modulate synaptic transmission. It remains unknown whether Gbetagamma specificity in vivo is due to specific Gbetagamma isoform-receptor associations or to spatial separation of distinct Gbetagamma pathways through macromolecular interactions. We thus sought to determine how Gbetagamma signaling pathways within axons remain distinct from one another. In rat hippocampal CA1 axons, GABA(B) receptors (GABA(B)Rs) inhibit presynaptic Ca(2+) entry, and we have now demonstrated that 5-HT(1B) receptors (5-HT(1B)Rs) liberate Gbetagamma to interact with SNARE complex C terminals with no effect on Ca(2+) entry. Both GABA(B)Rs and 5-HT(1B)Rs inhibit Ca(2+)-evoked neurotransmitter release, but 5-HT(1B)Rs have no effect on Sr(2+)-evoked release. Sr(2+), unlike Ca(2+), does not cause synaptotagmin to compete with Gbetagamma binding to SNARE complexes. 5-HT(1B)Rs also fail to inhibit release following cleavage of the C terminus of the SNARE complex protein SNAP-25 with botulinum A toxin. Thus, GABA(B)Rs and 5-HT(1B)Rs both localize to presynaptic terminals, but target distinct effectors. We demonstrate that disruption of SNARE complexes and vesicle priming with botulinum C toxin eliminates this selectivity, allowing 5-HT(1B)R inhibition of Ca(2+) entry. We conclude that receptor-effector specificity requires a microarchitecture provided by the SNARE complex during vesicle priming.

Infusion of the serotonin1B (5-HT1B) agonist CP-93,129 into the parabrachial nucleus potently and selectively reduces food intake in rats.[Pubmed:9566817]

Psychopharmacology (Berl). 1998 Apr;136(3):304-7.

Unilateral infusion of the selective 5-HT1B agonist, CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo[3,2-b]pyrid-5-one) into the parabrachial nucleus (PBN) of the pons reduced food consumption by rats. The hypophagia was dose-related (ED50 approximately 1 nmol) and associated with fewer observations of feeding and more periods of inactivity. Water intake, grooming and exploratory activity were unaffected. CP-93,129 also decreased food intake when injected into the hypothalamic paraventricular nucleus, but this action was 50-fold less potent than administration into the PBN. Autoradiography demonstrated 5-HT1B sites in the PBN; this binding was displaced by CP-93,129. The results implicate parabrachial 5-HT1B receptors in mediating serotonergic enhancement of satiation.