Since high-affinity adenosine A2 receptors (A2u) are localized exclusively in dopamine-rich regions in the central nervous system and mediate inhibition of locomotor activity, we have examined the effect of A2 receptor activation on D1 and D2 receptor binding in membrane preparations of the rat striatum. The A2a agonist 2-p-(2-carboxyethyl)phen- ethylaminoJ-5'-N-ethylcarboxamidoadenosine (CGS 21680) Adenosine has been shown to function as a neuromodulator in many areas of the mammalian central nervous system (1-3). These actions of adenosine are mediated by receptors that can be subdivided into Al and A2 subtypes based on relative agonist and antagonist potencies (4, 5). Al activation inhibits and A2 activation stimulates adenylate cyclase (4, 6, 7). The A2 receptors have been further subclassified into high-affinity (A2a) and low-affinity (A2b) receptors, based on agonist potencies with regard to adenylate cyclase activation (4) and receptor binding (5). The A2b receptors are widely distributed in the brain and mediate the stimulatory action of high concentrations of adenosine agonists on cAMP formation, which could affect dopamine release and synthesis (8,9). In contrast, A2a receptors are exclusively localized to dopamine-innervated areas ofthe central nervous system (10, 11), with a postsynaptic distribution (12) similar to that of postsynaptic D1 and D2 receptors (13). By using in situ hybridization the recently cloned A2a receptors (14) have been found to be localized to striatal medium-sized neurons (15).Adenosine agonists inhibit, whereas adenosine antagonists, including caffeine, enhance spontaneous (16, 17) and dopamine-induced locomotor activity (16,(18)(19)(20). The potencies of adenosine agonists in producing hypomotility correlate with their affinities for Au adenosine receptors (21,22), suggesting that A2. receptors mediate most of the behavioral effects of adenosine agonists. The hypomotility induced by adenosine agonists resembles that induced by classical neuroleptics (22), which act by blocking postsynaptic D2 receptors (23). In fact, behavioral evidence for a negative interaction between postsynaptic A2. and D2 receptors has recently been obtained using acutely reserpinized mice (24,25). Since activation of postsynaptic D2 receptors seems to be a necessary step for locomotor behavior, a negative interaction between postsynaptic A2. and D2 receptors could explain the hypomotility induced by adenosine agonists and the enhancement of locomotor activity induced by adenosine antagonists, including caffeine (24,25).In contrast to the A2a receptor, the D2 receptor mediates an inhibition of adenylate cyclase (26

With the aim of developing inhibitors of vasopressin- and oxytocin-induced uterine activity, 17 analogues of 1-deamino-oxytocin were synthesized by the solid-phase method. Modifications were made at positions 2, O-methyltyrosine (Tyr(OMe] and O-ethyltyrosine (Tyr(OEt],D-Tyr,D-Tyr(OEt),D-Trp; 4, Val,Thr and 8, Orn,Cit,Arg,D-Arg. The analogues were tested for antiuterotonic activity in vitro and in vivo in the rat and in vitro on myometrial strips from non-pregnant women and pregnant women at term. Their selectivity was also investigated in blood pressure and antidiuretic bioassays in rats. Results were compared with those from an original antiuterotonic analogue 1-deamino-2-Tyr(OEt)-oxytocin (d(OEt)-oxytocin). In the rat in vitro and in vivo all analogues possessed higher antiuterotonic activity than d(OEt)-oxytocin. The negative logarithm of the molar concentration of the antagonist which reduced the effect of a dose of agonist to that of half the dose (pA2) was between 7.6 and 8.9 for all the new inhibitors compared with 7.2 for d(OEt)-oxytocin. The highest pA2 value was found for 1-deamino-2-Tyr(OMe)-8-Orn-oxytocin (8.9 +/- 0.2, S.E.M.) and 1-deamino-2-Tyr(OEt)-4-Thr-8-Orn-oxytocin (8.9 +/- 0.6). In myometrium from non-pregnant women the most potent peptide was 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (17.2 +/- 2.0 times more potent that d(OEt)-oxytocin). In myometrium from pregnant women the inhibitory effects of the majority of the analogues were less pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)

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When today’s engineering design process involves information generated by a wide range of computational tools it is necessary to find tools and methods to integrate this information efficiently. Recent advances in the standardization of distributed application development give new potential to deal with this issue. The programming interfaces made available for this communication are referred to as Web Services and implies a straightforward way to exchange design data between engineers, simulation tools and other distributed information resources. The paper illustrates how simulation models and tools can be deployed as web services and how functionality and design data can be exchanged between these tools and accessed from standard desktop applications. An integration framework is presented where distributed services are integrated and the computational process is explicitly defined and executed. This model integration service also enables design optimization using the COMPLEX algorithm and Monte-Carlo simulation for probabilistic analysis of the design. The presented framework is built on open standards and gives new potential to already existing tools. By wrapping computational tools into a web service they can be integrated and accessed by any other application supporting web-service communication regardless of computer platform or operating system.

In this paper, it is illustrated how computational design methods such as design optimization and probabilistic analysis is applied to system simulation models in a web based framework. Special emphasis is given models defined in the Modelica modeling language. An XML-based information system for representation and management of design data for use together with Modelica models as well as other types of models is proposed. This approach introduces a separation between the model of the system and data related to the design of the product. This is important in order to facilitate the use of computational methods in a generic way. A web based framework for integration of simulation models and computational methods is further illustrated. The framework is based on open standards for distributed computing and enables so-called service oriented architecture. Finally, an example is presented, where design optimization and probabilistic analysis is carried out on a Modelica model of an aircraft actuation system using the proposed and implemented tools and methods.