AMENDMENT NO. 1 TO
                              COOPERATION AGREEMENT
                              ---------------------

                                                              Amendment   No.  1
                                                     dated and  effective  as of
                                                     August  10,  1998,  between
                                                     SYNAPTIC     PHARMACEUTICAL
                                                     CORPORATION,  a corporation
                                                     organized under the laws of
                                                     the   State   of   Delaware
                                                     ("SYNAPTIC"),           and
                                                     GRUNENTHAL      GMBH,     a
                                                     corporation organized under
                                                     the  laws  of  the  Federal
                                                     Republic     of     Germany
                                                     ("GRUNENTHAL").

                                   Witnesseth
                                   ----------

         WHEREAS, SYNAPTIC and GRUNENTHAL are parties to a Cooperation Agreement
dated as of January 12, 1998 (the  "Agreement").  Capitalized terms used and not
defined in this Amendment No. 1 shall have the meanings  ascribed to them in the
Agreement;

         WHEREAS, under Section 2.6.4 of the Agreement, SYNAPTIC is permitted to
use COMPOUNDS  provided by GRUNENTHAL for purposes  other than the  cooperation,
and to commercialize any product resulting from such use, without  obligation to
GRUNENTHAL,  financial or otherwise, unless such product incorporates a compound
covered  by an issued  GRUNENTHAL  PATENT  RIGHT,  in which case  GRUNENTHAL  is
entitled to receive compensation as provided in Section 2.6.4;

         WHEREAS,  the  parties  have  determined  that  it may  be in the  best
interests  of the  cooperation  for  GRUNENTHAL  to send  certain  compounds  to
SYNAPTIC for screening and/or other testing  promptly  following their synthesis
and prior to the  preparation  and filing by GRUNENTHAL of a patent  application
covering such compounds;

         WHEREAS,   the  parties  recognize  that  inventions  may  result  from
SYNAPTIC's  use of such  COMPOUNDS  and that  SYNAPTIC may desire to prepare and
file patent applications covering such inventions;

         WHEREAS,  the parties have determined  that, with respect to certain of
such  inventions,  GRUNENTHAL  should be  entitled  to receive  compensation  as
provided in Section 2.6.4,  notwithstanding that such inventions are not covered
by an issued  GRUNENTHAL  PATENT RIGHT,  as currently  defined in the Agreement,
and, accordingly, desire to amend the Agreement to provide for such compensation
and to make certain changes relating thereto;

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         WHEREAS,  the Agreement  contemplates that SYNAPTIC and GRUNENTHAL will
from time to time  evaluate  AVAILABLE  TARGETS for the purpose of assessing the
desirability of initiating new PROJECTS which have as their focus one or more of
such AVAILABLE TARGETS;

         WHEREAS,  in  connection  with  and in  order  to  facilitate  any such
evaluation,  SYNAPTIC may provide to GRUNENTHAL  biological materials comprising
or relating to an AVAILABLE TARGET; and

         WHEREAS,  the parties  desire to amend the Agreement to further  define
their rights and obligations as they relate to any such biological materials.

         NOW,  THEREFORE,  in  consideration  of the  premises  and  the  mutual
covenants hereinafter set forth, the parties agree as follows:

1.       SYNAPTIC's Use of COMPOUNDS  Provided by  GRUNENTHAL.  Section 2.6.4 of
         the Agreement is hereby amended to read in its entirety as follows:

         "2.6.4   SYNAPTIC's Use of COMPOUNDS Provided by GRUNENTHAL.

                  (a)      SYNAPTIC shall be permitted to use COMPOUNDS provided
                           to  SYNAPTIC  by   GRUNENTHAL   and  to   exclusively
                           commercialize any product  developed  therefrom by or
                           on behalf of SYNAPTIC (a "SYNAPTIC PRODUCT"), without
                           compensation  to GRUNENTHAL,  financial or otherwise,
                           so long as the  mechanism  of  action  of the  active
                           compound  or  compounds  in  such  SYNAPTIC   PRODUCT
                           involves:

                           (i)      an EXCLUDED TARGET; or

                           (ii)     an AVAILABLE  TARGET and such product is not
                                    useful for the alleviation of PAIN.

                  (b)      Notwithstanding anything to the contrary contained in
                           paragraph (a) above, if:

                           (i)      the  active  compound,  or the  use of  such
                                    active compound, in such SYNAPTIC PRODUCT is
                                    claimed  in  terms of a  chemical  structure
                                    either  as a  species  or as a  member  of a
                                    genus  in  an  issued   PATENT  RIGHT  which
                                    GRUNENTHAL  owns,  solely  or  jointly  with
                                    SYNAPTIC; and

                           (ii)     GRUNENTHAL is not  independently of SYNAPTIC
                                    commercializing  a product which  includes a
                                    different  compound  claimed in such  PATENT
                                    RIGHT for the same therapeutic indication

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                                    for which the SYNAPTIC PRODUCT is commer-
                                    cialized, then SYNAPTIC shall pay GRUNENTHAL
                                    a royalty of:

                                    (A)     3% of the NET SALES of such SYNAPTIC
                                            PRODUCT in  countries  in which such
                                            issued   GRUNENTHAL   PATENT   RIGHT
                                            exists  if  SYNAPTIC   independently
                                            commercializes     such     SYNAPTIC
                                            PRODUCT; or

                                    (B)     33% of any  royalty  which  SYNAPTIC
                                            receives   from  a  third  party  in
                                            respect of any such PATENT  RIGHT if
                                            SYNAPTIC    licenses    the   issued
                                            GRUNENTHAL  PATENT  RIGHT to a third
                                            party.

                  (c)      In   the   event   that,   as   a   result   of   its
                           commercialization  of any SYNAPTIC PRODUCT,  SYNAPTIC
                           would otherwise be required to pay GRUNENTHAL,  under
                           both Section 2.6.2 and this Section 2.6.4, 33% of any
                           royalty  which  it  receives  from a third  party  in
                           respect    of    such    SYNAPTIC    PRODUCT,    then
                           notwithstanding  such  sections,  SYNAPTIC  shall  be
                           required to pay  GRUNENTHAL  33% of such royalty only
                           under this Section 2.6.4."

2.       Patent Rights. The section reference "7.1.3" of the Agreement is hereby
         renamed  "7.1.4" and there is hereby  added  immediately  prior to such
         Section 7.1.4 the following new Section 7.1.3:

         "7.1.3   Inventions Resulting from SYNAPTIC's Use of Compounds Provided
                    by GRUNENTHAL.
                  --------------------------------------------------------------
                  Notwithstanding  the  provisions  of Sections 7.1.1 and 7.1.2,
                  GRUNENTHAL  and  SYNAPTIC  agree  that  PATENT  RIGHTS for any
                  invention  which  results  from  SYNAPTIC's  use  of COMPOUNDS
                  provided  by  GRUNENTHAL  pursuant  to  Section 2.6.4 shall be
                  jointly owned by  GRUNENTHAL  and SYNAPTIC  to the extent that
                  the PATENT RIGHTS relating to such invention claim in terms of
                  a chemical structure a compound  or  the  use  of  a  compound
                  provided  to  SYNAPTIC  by  GRUNENTHAL.  For  purposes  of the
                  preceding sentence, a compound will  be considered  to  be  so
                  claimed if it is claimed either as a species or as a member of
                  a genus  having  such  chemical  structure.  SYNAPTIC shall be
                  responsible  for  preparing  all  draft   patent  applications
                  encompassed within such PATENT RIGHTS and shall  provide  such
                  drafts to GRUNENTHAL  for  review and comment prior to filing.
                  SYNAPTIC and  GRUNENTHAL  shall discuss and agree which person
                  or persons should be named  as  inventor  or inventors on such
                  patent applications in accordance  with  applicable principles
                  of inventorship  under U.S. Patent Law.  All expenses relating
                  to   the  preparation,  filing,   prosecution,  extension  and
                  maintenance of such jointly-owned

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                  patent applications and any patents  granted  thereon shall be
                  borne by SYNAPTIC. If SYNAPTIC determines:

                  (a)     not to file a patent application for such an invention
                          in any of the TERRITORIES;

                  (b)     not  to continue prosecution or maintenance thereof in
                          any of the TERRITORIES; or

                  (c)     not to extend any patent granted thereon in any of the
                          TERRITORIES,

                  then SYNAPTIC shall promptly notify  GRUNENTHAL and GRUNENTHAL
                  shall be given  the  opportunity  to seek  and  pursue  patent
                  protection  on such  invention  in such  territory  at its own
                  expense.   In  the  event   GRUNENTHAL   pursues  such  patent
                  protection,  ownership of the PATENT RIGHTS for such invention
                  in any such  territory  shall be  assigned to  GRUNENTHAL  and
                  GRUNENTHAL  shall  thereafter be the sole owner of such PATENT
                  RIGHTS in such territory."

3.       Limitations  on Use of  Certain  Information.  There  is  hereby  added
         immediately  following Section 2.6.7 of the Agreement the following new
         Section 2.7:

                  "2.7     Limitations  on  Use  of  Information  Resulting from
                             Evaluation of  Available Targets.
                           -----------------------------------------------------
                           In  connection  with the evaluation by the parties of
                           AVAILABLE  TARGETS  for  purposes  of  assessing  the
                           desirability of  initiating new PROJECTS that have as
                           their focus one or more of such AVAILABLE TARGETS, it
                           is  contemplated  that   SYNAPTIC   may   provide  to
                           GRUNENTHAL   biological    materials   comprising  or
                           relating to such TARGETS. In the event any biological
                           materials are  so  provided, GRUNENTHAL  acknowledges
                           and agrees that:

                           (a)      except to the extent  necessary or desirable
                                    to  perform  the  evaluation,  no  right  or
                                    license  under  any  patent,   copyright  or
                                    trademark  of SYNAPTIC is granted,  or to be
                                    construed as being granted,  by implication,
                                    estoppel or otherwise,  to GRUNENTHAL by the
                                    terms of this Agreement; and

                           (b)      results or inventions  derived,  directly or
                                    indirectly,  from any assays  involving  the
                                    use of such biological materials may be used
                                    by  GRUNENTHAL  solely for  purposes  of the
                                    evaluation and in connection  with a PROJECT
                                    which has as its focus the AVAILABLE  TARGET
                                    that is the  subject of the  evaluation  and
                                    may not be used by GRUNENTHAL  for any other
                                    purpose; and


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                           (c)      it will not develop any compounds identified
                                    as agonists or antagonists of such AVAILABLE
                                    TARGET  pursuant to any assay  conducted  as
                                    part of the evaluation  except in connection
                                    with a PROJECT  which has as its focus  such
                                    AVAILABLE TARGET."

4.       Confidentiality.  Section 11.1 of the  Agreement  is hereby  amended by
         adding at the end thereof the following new sentence:

                  "For purposes of this Article 11, the term "information" shall
                  include  all data and  other  information,  whether  disclosed
                  orally  or  in  written  or  graphic  form,  as  well  as  all
                  biological   materials,    including,    without   limitation,
                  eukaryotic   expression   vectors  containing  cDNAs  encoding
                  receptors, bacterial stocks and cell lines."

5.       Effect of Amendment and Supplement.

         (a)      From and after the date first written above, all references in
                  the  Agreement  to "this  AGREEMENT,"  "hereunder,"  "hereof,"
                  "hereof,"  "herein,"  or words of similar  import,  shall be a
                  reference to the  Agreement,  as amended by this Amendment No.
                  1.

         (b)      Except as expressly amended and supplemented by this Amendment
                  No. 1, the Agreement shall remain in full force and effect and
                  unchanged.



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         IN WITNESS WHEREOF,  the parties have caused this Amendment No. 1 to be
executed and delivered as of the date first written above.



                                  SYNAPTIC PHARMACEUTICAL CORPORATION

                                  By:/s/ Kathleen P. Mullinix
                                     -----------------------------
                                  Name:  Kathleen P. Mullinix
                                  Title: Chairman, President and
                                           Chief Executive Officer



                                  GRUNENTHAL GMBH.

                                  By: /s/ Dr. E. Paques     /s/ C. Baguette
                                     --------------------------------------
                                  Name: Dr. E. Pacques         C. Baguette
                                  Title: Managing Director  Dir. Bus. Dvlpt.






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