The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.

The preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Variations of the ring size of the azacycle and substitution on the pyridine had dramatic effects on receptor binding affinity with IC50s at the alpha4beta2 nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidinyl)oxy)pyridine 27f with an IC50 of 22 nM.

Abstract: We have recently reported evidence that a very high affinity interaction between the β‐amyloid peptide Aβ1‐42 and the α7 nicotinic acetylcholine receptor (α7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of Aβ1‐42 to α7nAChR and α4β2nAChR were determined using the subtype‐selective nicotinic receptor ligands [3H]methyllycaconitine and [3H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. Aβ1‐42 bound to the α7nAChR with exceptionally high affinity, as indicated by Ki values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the α7nAChR, the affinity of Aβ1‐42 for the α4β2nAChR was ∼5,000‐fold lower, as indicated by corresponding Ki values of 30 and 23nM. The results of this study support the concept that an exceptionally high affinity interaction between Aβ1‐42 and α7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.