Both relaxin-3 and its receptor (GPCR135) are expressed predominantly in brain regions known to play important roles in processing sensory signals. Recent studies have shown that relaxin-3 is involved in the regulation of stress and feeding behaviors. The mechanisms underlying the involvement of relaxin-3/GPCR135 in the regulation of stress, feeding, and other potential functions remain to be studied. Because relaxin-3 also activates the relaxin receptor (LGR7), which is also expressed in the brain, selective GPCR135 agonists and antagonists are crucial to the study of the physiological functions of relaxin-3 and GPCR135 in vivo. Previously, we reported the creation of a selective GPCR135 agonist (a chimeric relaxin-3/ INSL5 peptide designated R3/I5). In this report, we describe the creation of a high affinity antagonist for GPCR135 and GPCR142 over LGR7. This GPCR135 antagonist, R3(B⌬23-27)R/I5, consists of the relaxin-3 B-chain with a replacement of Gly 23 to Arg, a truncation at the C terminus (Gly 24 -Trp 27 deleted), and the A-chain of INSL5. In vitro pharmacological studies showed that R3(B⌬23-27)R/I5 binds to human GPCR135 (IC 50 ‫؍‬ 0.67 nM) and GPCR142 (IC 50 ‫؍‬ 2.29 nM) with high affinity and is a potent functional GPCR135 antagonist (pA2 ‫؍‬ 9.15) but is not a human LGR7 ligand. Furthermore, R3(B⌬23-27)R/I5 had a similar binding profile at the rat GPCR135 receptor (IC 50 ‫؍‬ 0.25 nM, pA2 ‫؍‬ 9.6) and lacked affinity for the rat LGR7 receptor. When administered to rats intracerebroventricularly, R3(B⌬23-27)R/I5 blocked food intake induced by the GPCR135 selective agonist R3/I5. Thus, R3(B⌬23-27)R/I5 should prove a useful tool for the further delineation of the functions of the relaxin-3/GPCR135 system.Relaxin-3 (R3) 2 (1) is the most recently identified member of the insulin-relaxin peptide family. Both relaxin-3 and its receptor, GPCR135 (2), are predominantly expressed in the brain (2, 3). GPCR135, an inhibitory receptor, is expressed in many regions of the rodent brain such as the superior colliculus, sensory cortex, olfactory bulb, amygdale, and paraventricular nucleus (4 -6), suggesting potential physiological involvement in neuroendocrine and sensory processing. Recent in vivo studies have further shown that relaxin-3 and GPCR135 are involved in the stress response and in regulation of feeding. More specifically, water restraint stress or intracerebroventricular corticotrophin-releasing factor (CRF) infusion induces relaxin-3 expression in cells of the nucleus incertus, a region where CRF receptor-1 is also expressed (7), and central administration of relaxin-3 induces feeding in rat (8, 9). These findings suggest that GPCR135 and relaxin-3 may be involved in multiple physiological processes, some of which might be as yet unknown.In vitro relaxin-3 activates GPCR135 (2), GPCR142 (10), and LGR7 (11) receptors. The predominant brain expression of both relaxin-3 and GPCR135, coupled with their high affinity interaction, strongly suggests that relaxin-3 is the endogenous ligand for GPCR135 (2). Phar...

The present article reviews two classes of semiclassical (mixed quantum mechanical/classical) methods for investigating multielectronic-state dynamics:  the trajectory surface-hopping (TSH) method and the time-dependent self-consistent field (TDSCF) method. The recent availability of accurate quantum mechanical dynamics calculations for a variety of realistic three-body two-state potential energy matrices has allowed an assessment of the validity of semiclassical multisurface dynamics methods that are applicable to larger systems. These studies indicate that Tully's fewest switches algorithm is the best available TSH method and that the Ehrenfest method is the best previously available TDSCF method. The fewest switches surface-hopping method has relatively small errors even when it is not the best method while the Ehrenfest TDSCF method tends to have larger errors when it is not the best. However, the fewest switches algorithm involves unphysical discontinuities in momenta, and the results may depend on the choice of representation. Furthermore, the surface-hopping algorithm is frequently frustrated in its attempt to maintain ensemble-average self-consistency. The Ehrenfest method removes all these troublesome aspects but at the cost of producing unphysical mixed states, which are responsible for its larger errors in observables. A recently introduced TDSCF method, the continuous surface-switching method, removes the unphysical mixed states of the Ehrenfest method, and in initial tests it produces results that are systematically better than those calculated by the Ehrenfest method. The present article illustrates several of these aspects of nonadiabatic trajectory methods pictorially.

We present a new method called the natural decay of mixing (NDM) method for introducing decoherence effects into the semiclassical Ehrenfest self-consistent potential method. The NDM method is similar in spirit to two recently developed methods, the continuous surface switching (CSS) and continuous surface switching II (CSS2) methods, but, like the pure semiclassical Ehrenfest method, it involves only a single variable that serves as both the weight of an electronic state and its electronic population. We demonstrate how this allows the NDM method to be applied to systems where the CSS and CSS2 methods cannot be applied, and also to cases where the CSS and CSS2 methods would be prohibitively expensive. The method is tested for electronically nonadiabatic processes, both reactive and nonreactive, and in a wider context it contributes to the rapidly blossoming fields of quantum measurement and hybrid quantum/classical algorithms for the dynamics of complex systems.

A family of four weakly coupled electronically nonadiabatic bimolecular model photochemical systems is presented. Fully converged quantum mechanical calculations with up to 25 269 basis functions were performed for full-dimensional atom-diatom collisions to determine the accurate scattering dynamics for each of the four systems. The quantum mechanical probabilities for electronically nonadiabatic reaction and for nonreactive electronic deexcitation vary from 10 Ϫ1 to 10 Ϫ5 . Tully's fewest-switches ͑TFS͒ semiclassical trajectory surface-hopping method ͑also called molecular dynamics with quantum transitions or MDQT͒ is tested against the accurate quantal results. The nonadiabatic reaction and nonreactive deexcitation events are found to be highly classically forbidden for these systems, which were specifically designed to model classically forbidden electronic transitions ͑also called frustrated hops͒. The TFS method is shown to systematically overestimate the nonadiabatic transition probabilities due to the high occurrence of frustrated hops. In order to better understand this problem and learn how to best minimize the errors, we test several variants of the TFS method on the four new weakly coupled systems and also on a set of three more strongly coupled model systems that have been presented previously. The methods tested here differ from one another in their treatment of the classical trajectory during and after a frustrated hopping event. During the hopping event we find that using a rotated hopping vector results in the best agreement of semiclassical and quantal results for the nonadiabatic transition probabilities. After the hopping event, we find that ignoring frustrated hops instead of reversing the momentum along the nonadiabatic coupling vector results in the best agreement with the accurate quantum results for the final vibrational and rotational moments. We also test the use of symmetrized probabilities in the equations for the TFS hopping probabilities. These methods systematically lead to increased error for systems with weakly coupled electronic states unless the hopping probabilities are symmetrized according to the electronic state populations.