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Bolus-administered intracerebroventricular (ICV) relaxin-3 has been reported to increase feeding. In this study, to examine the role of relaxin-3 signaling in energy homeostasis, we studied the effects of chronically administered ICV relaxin-3 on body weight gain and locomotor activity in rats. Two groups of animals received vehicle or relaxin-3 at 600 pmol/head/day, delivered with Alzet osmotic minipumps. In animals receiving relaxin-3, food consumption and weight gain were statistically significantly higher than those in the vehicle group during the 14-day infusion. During the light phase on days 2 and 7 and the dark phase on days 3 and 8, there was no difference in locomotor activity between the two groups. Plasma concentrations of leptin and insulin in rats chronically injected with relaxin-3 were significantly higher than in the vehicle-injected controls. These results indicate that relaxin-3 up-regulates food intake, leading to an increase of body weight and that relaxin-3 antagonists might be candidate antiobesity agents.

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Conformational analyses and molecular-shape comparisons were carried out on an analogue series of indanone-benzylpiperidine inhibitors of acetylcholinesterase (AChE). It was possible to define an active conformation with respect to the flexible geometry of the benzylpiperidine moiety, as well as an active conformation of the indanone ring-piperidine ring substructure for analogues having a single spacer group between these rings. No active conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine rings. Still, a receptor binding model can be constructed for all indanone and piperidine ring substructures. The postulated active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is close to the crystal structures of 1a with respect to the indanone-piperidine substructure, but differs from the crystal structures for the benzylpiperidine moiety. However, the crystal conformations and the postulated active conformation of the benzylpiperidine portion of the AChE inhibitor are estimated to be about equally stable. A trans-decalin analogue of 1a can adopt the postulated active conformation as shown by calculation and as seen in its crystal structure. The inactivity of this analogue is explained by the added steric size of the decalin unit and/or the time-average valence geometry behavior at the spiro junction to the indanone ring.

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The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.