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.