ABSTRACT
(S)-(2)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine HCl (SIB-1508Y, Altinicline), is a subtype-selective neuronal nicotinic acetylcholine receptor (nAChR) agonist. In rodents, SIB-1508Y exhibited antidepressant activity, reversed age-related decrements in vigilance, and improved motor and cognitive function in primate models of Parkinson's disease. The goal of the study was to explore neurochemical effects of SIB-1508Y and its isomer, SIB-1680WD. In vitro, SIB-1508Y increased dopamine (DA) release from slices of rat striatum, nucleus accumbens (NAc), olfactory tubercles (OT) and prefrontal cortices (PFC) in a concentration-dependent manner. Relative to its robust effects on DA release from various brain regions, SIB-1508Y was minimally effective at increasing NE release from hippocampus or PFC, and 5-HT release from PFC. SIB-1680WD was less potent and efficacious than SIB-1508Y, but did not act as a partial agonist. Subcutaneous injection of SIB-1508Y (10 mg/kg) increased striatal DA release and this release was sensitive to blockade by the non-competitive nAChR antagonist, mecamylamine (Mec). SIB-1508Y also increased hippocampal ACh release selectively without affecting striatal ACh release. Hippocampal ACh release evoked by SIB-1508Y was attenuated by nAChR antagonists Mec and Dihydro-beta-erythroidine (DHbetaE), and also by the DA D1 receptor antagonist, SCH-23390. These results are consistent with previously established pharmacology of nAChR regulation of hippocampal ACh release. Repeated administration of SIB-1508Y did not result in an enhanced striatal DA release or hippocampal ACh release. In summary, the abilities of SIB-1508Y to release multiple neurotransmitters in distinct brain regions may contribute to its behavioral profile.
Subject(s)
Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Pyrrolidines/pharmacology , Receptors, Nicotinic/drug effects , Acetylcholine/metabolism , Animals , Brain Chemistry/drug effects , Chromatography, High Pressure Liquid , Dopamine/metabolism , Dose-Response Relationship, Drug , Hippocampus/drug effects , Hippocampus/metabolism , Injections, Subcutaneous , Male , Microdialysis , Neostriatum/drug effects , Neostriatum/metabolism , Neurotransmitter Agents/metabolism , Nicotinic Agonists/administration & dosage , Norepinephrine/metabolism , Pyridines/administration & dosage , Pyrrolidines/administration & dosage , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereotaxic TechniquesABSTRACT
SIB-1663 ([+/-]-7-methoxy-2,3,3a,4,5,6,9b-hexahydro-1H-pyrrolo-[3,2h]-isoquinoline) is a conformationally restricted analog of nicotine (NIC). SIB-1663 exhibited modest affinities to cholinergic receptors (K(i) values displacing the binding of [(3)H]-nicotine (NIC) and [(3)H]-quinuclinidylbenzilate (QNB) binding were 1.0+/-0.3 and 2.6+/-0.3 microM, respectively) with no appreciable affinity to nearly 40 other receptors. SIB-1663 selectively activated alpha2beta4 and alpha4beta4 human recombinant neuronal nicotinic acetylcholine receptors (nAChRs) with no appreciable activation of alpha4beta2 nAChRs, the presumed high-affinity nAChRs in rodent brain. These properties led us to examine profile of SIB-1663 in native preparations. SIB-1663 increased DA release from the rat striatum (STR) and olfactory tubercles and NE release from hippocampus, thalamus and prefrontal cortex (PFC). SIB-1663 was equiefficacious to NIC in STR-DA and PFC-NE release assays and less efficacious than NIC in other release assays. SIB-1663 appeared to be partial agonist in the hippocampal NE release assay. SIB-1663-induced neurotransmitter release in vitro was relatively insensitive to the nAChR antagonists, mecamylamine (MEC) or dihydro-beta-erythroidine (DHbetaE) providing equivocal evidence for nAChR activity. SIB-1663 (3-30 mg/kg, s.c.) increased locomotor activity in naive rats in a novel environment, increased ipsilateral turning in rats with unilateral 6-OHDA nigrostriatal lesion and increased withdrawal latencies in the tail-flick assay. The in vivo effects of SIB-1663 in these assays showed varying degrees of sensitivity to nAChR antagonists in that the locomotor activity and turning behavior of SIB-1663 were partially sensitive to MEC, whereas the antinociceptive activity was completely sensitive to MEC. In addition, SIB-1663 (s.c. or i.c.v.) attenuated antinociceptive activity NIC given by the same route suggesting a partial agonist activity. SIB-1663 also increased the retention of avoidance learning in normal rats when administered immediately after the acquisition session. These data indicate that SIB-1663, a conformationally restricted analog of NIC, with distinct nAChR subtype selectivity from NIC exhibits contrasting pharmacology with some of its in vivo actions involving nAChRs.
Subject(s)
Nicotine/analogs & derivatives , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Analgesics/metabolism , Analgesics/pharmacology , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Male , Molecular Conformation , Nicotine/chemistry , Nicotine/metabolism , Nicotinic Agonists/metabolism , Pain Measurement/drug effects , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Sprague-DawleyABSTRACT
SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which displaced the binding of [3H]nicotine (NIC) to the rat brain nAChRs with an IC(50) value of 110 nM with no appreciable affinity to the alpha7 nAhRs. SIB-1553A showed modest affinity for histaminergic (H3) and serotonergic (5-HT1 and 5-HT2) receptors, and sigma binding sites. In calcium flux assays, SIB-1553A (0.1-5 microM), in contrast to nicotine, showed a greater selectivity for beta4-subunit containing recombinant hnAChRs (alpha2beta4, alpha3beta4 and alpha4beta4) vs. beta2-subunit containing nAChRs (alpha4beta2 and alpha3beta2) both in terms of efficacy and potency. While NIC (10-30 microM) and epibatidine (0.01-0.1 microM) fully activated human muscle-type AChRs expressed by RD cell line, SIB-1553A was virtually ineffective for up to >100 microM and elicited less than 10% of the response due to suberyldicholine. SIB-1553A (< or =30 microM) evoked [3H]DA release from striatum, olfactory tubercles and prefrontal cortex (PFC), and [3H]NE release from hippocampus and PFC, and this evoked release was sensitive to mecamylamine (MEC). SIB-1553A-evoked neurotransmitter release exhibited region- and transmitter-specific antagonism by dehydro-beta-erythroidine (DHbetaE). SIB-1553A was less efficacious than NIC at evoking [3H]NE from the rat hippocampus and antagonized NIC response upon co-application implying partial agonist properties. SIB-1553A did not evoke basal [3H]ACh release from the rat striatum or hippocampus, but attenuated NMDA-evoked [3H]ACh release from the rat striatum. SIB-1553A did not inhibit rat brain cholinesterase for up to 1 mM. Multiple receptor affinities and release of several neurotransmitters may underlie the cognitive-enhancing effects of SIB-1553A documented in rodent and primate models.